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Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations. Historically, the mainstay of therapy for both conditions has been systemic glucocorticoids. However, recent availability of biologics that directly or indirectly target eosinophils has provided new avenues to pursue improved outcomes with decreased toxicity. In this article, we summarize the evidence supporting the use of specific biologics in HES and/or EGPA and provide a framework for their clinical use in patients., Competing Interests: Disclosure The authors have nothing to disclose. This work was supported in part by the Division of Intramural Research, NIAID, NIH., (Published by Elsevier Inc.)

Eosinophilic gastrointestinal diseases (EGIDs) encompass a group of disorders characterized by an abnormal accumulation of eosinophils in various parts of the gastrointestinal tract. EGIDs present with a wide range of symptoms such as abdominal pain, vomiting, diarrhea, difficulty swallowing, and food impaction. Monoclonal antibodies, targeting inflammatory cytokines or eosinophils, are the next emerging therapy for EGIDs. The only Food and Drug Administration-approved monoclonal antibody is dupilumab, and it has been approved for the treatment of eosinophilic esophagitis (EoE). In this article, the authors will discuss biologics that have been used in the treatment of eosinophilic gastrointestinal diseases., Competing Interests: Disclosures The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Our modern understanding of asthma mainly concerns identification of inflammatory endotype to guide management. The distinction mostly concerns identification of type-2 inflammation, for which different biomarkers have been well characterized. Blood eosinophils corroborate activity in the interleukin (IL)-5 axis while fraction of exhaled nitric oxide is indicative of the IL-4/IL-13 axis, giving us an indication of activity in these distinct but complementary pathways. These biomarkers predict disease activity, with increased risk of exacerbations when elevated, and a further, multiplicative increase when both are elevated. Serum immunoglobulin E is also implicated in this pathway, and can represent allergen-related stimulation., Competing Interests: Disclosure In the last 5 years, I D. Pavord has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca, Aerocrine, Almirall, Sanofi/Regeneron, Menarini, and GSK and payments for organizing educational events from AZ, GSK, and Sanofi/Regeneron. He has received honoraria for attending advisory panels with Sanofi/Regeneron, Astra Zeneca, GSK, Merck, Circassia, Chiesi, and Areteia. He has received sponsorship to attend international scientific meetings from GSK, Astra Zeneca, and Sanofi/Regeneron. G. Lavoie has no conflicts of interests to declare regarding this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The subcellular distribution of CD30 on mast cells and the presence of eosinophils in cutaneous mastocytosis require further investigation, especially as the cell surface expression of CD30 is critical for the therapeutic response of systemic mastocytosis to brentuximab vedotin., Objective: Investigation of 147 biopsy specimens from 143 patients with cutaneous mastocytosis for mast cell density and distribution, frequency of CD30 expression, CD30 staining patterns, and presence and distribution of eosinophils. Correlation with clinical patterns., Methods: Retrospective multicenter immunohistochemical study of CD30 expression, eosinophils and basic clinical data in cutaneous mastocytosis., Results: CD30 expression was found in all samples (cut-off: ≥1%), whereby the staining was predominantly cytoplasmic in 99% of the samples. Additional membrane staining was detected in 62% of the samples. Surface expression of CD30 was more common in biopsy specimens with a high mast cell burden and in biopsy specimens with a higher CD30 expression rate. Eosinophils were admixed in 58% of the samples. Females and older patients showed a trend of a lower mast cell burden., Limitations: Retrospective study on formalin-fixed and paraffin-embedded tissue without functional analysis., Conclusion: Most cases of cutaneous mastocytosis show cell surface expression of CD30 expression and is, therefore, in principle, accessible for therapy with antibodies against CD30, provided the overall situation of the patient warrants., (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Inflammation is an established contributor to the pathophysiology of depression and the prevalence of depression in those with chronic inflammatory disease is two- to four-fold higher than the general population. Yet little is known about the neurobiological changes that confer depression or resilience to depression, that occur when episodes of heightened inflammation are frequent or span many years., Methods: We used an innovative combination of longitudinal resting state functional magnetic resonance imaging coupled to segmental bronchial provocation with allergen (SBP-Ag) to assess changes in resting state functional connectivity (rsFC) of the salience network (SN) caused by an acute inflammatory exacerbation in twenty-six adults (15 female) with asthma and varying levels of depressive symptoms. Eosinophils measured in bronchoalveolar lavage fluid and blood provided an index of allergic inflammation and the Beck Depression Inventory provided an index of depressive symptoms., Results: We found that in those with the highest symptoms of depression at baseline, SN rsFC declined most from pre- to post-SBP-Ag in the context of a robust eosinophilic response to challenge, but in those with low depressive symptoms SN rsFC was maintained or increased, even in those with the most pronounced SBP-Ag response., Conclusions: Thus, the maintenance of SN rsFC during inflammation may be a biomarker of resilience to depression, perhaps via more effective orchestration of large-scale brain network dynamics by the SN. These findings advance our understanding of the functional role of the SN during inflammation and inform treatment recommendations for those with comorbid inflammatory disease and depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Interleukin-33 (IL-33) is a pleiotropic molecule that plays various roles in the body. However, how exogenous IL-33 changes the tumor immune microenvironment remains unclear. Our study revealed that exogenous IL-33 exerts anti-tumor effects and effectively suppresses the progression of subcutaneous melanoma. scRNA-seq analysis revealed that exogenous IL-33 reduced neutrophils accumulation, thereby improving the inhibitory immune environment. Flow cytometry analysis revealed that exogenous IL-33 significantly increased the proportion of eosinophils and group 2 innate lymphoid cells (ILC2s). In addition, we identified genes encoding major histocompatibility complex (MHC) class II molecules in this group of ILC2s, suggesting that ILC2s may play a role in antigen presentation. In Il7r Cre Arg1 flox/flox mice, the decrease of ILC2s led to a reduction in the proportion of eosinophils. Furthermore, we found that exogenous IL-33 effectively promoted the differentiation of ILC2s and their accumulation in tumors, thereby enhancing the anti-tumor immune response. These findings may pave the way for developing new cancer immunotherapies that use IL-33 as an activator to enhance anti-tumor immune responses., (© 2024. The Author(s).)

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5 + ILC2s and TSLPR + ILC2s in eCOPD compared with neCOPD ( p < 0.05 and p < 0.01, respectively) and HSs ( p < 0.001 for both). In addition, we showed that IL-5 + ILC2s, IL-17RB + ILC2s and ST2 + ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

Introduction: Elevated blood eosinophil levels in patients with chronic obstructive pulmonary disease (COPD) with or without asthma are linked to increased exacerbations and the effectiveness of inhaled corticosteroid treatment. This study aimed to delineate the inflammatory cellular properties of eosinophils in patients with asthma-COPD overlap (ACO) and eosinophilic COPD (eCOPD)., Methods: Eosinophils were isolated from the peripheral blood of healthy volunteers, patients with non-eCOPD, and those with ACO/eCOPD. Multi-omics analysis involving transcriptomics, proteomics, and lipidomics was performed, followed by bioinformatic data analyses. In vitro experiments using eosinophils from healthy volunteers were conducted to investigate the molecular mechanisms underlying cellular alterations in eosinophils., Results: Proteomics and transcriptomics analyses revealed cellular characteristics in overall COPD patients represented by viral infection (elevated expression of sterol regulatory element-binding protein-1) and inflammatory responses (elevated levels of IL1 receptor-like 1, Fc epsilon receptor Ig, and transmembrane protein 176B). Cholesterol metabolism enzymes were identified as ACO/eCOPD-related factors. Gene Ontology and pathway enrichment analyses demonstrated the key roles of antiviral responses, cholesterol metabolism, and inflammatory molecules-related signaling pathways in ACO/eCOPD. Lipidomics showed the impaired synthesis of cyclooxygenase-derived mediators including prostaglandin E2 (PGE2) in ACO/eCOPD. In vitro assessment confirmed that IL-33 or TNF-α stimulation combined with IL-5 and IFN-γ stimulation induced cellular signatures in eosinophils in ACO/eCOPD. Atorvastatin, dexamethasone, and PGE2 differentially modulated these inflammatory changes., Discussion: ACO/eCOPD is associated with viral infection and an inflammatory milieu. Therapeutic strategies using statins and inhaled corticosteroids are recommended to control these pathogenic changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sunata, Miyata, Kawashima, Konno, Ishikawa, Hasegawa, Onozato, Otsu, Matsuyama, Sasaki, Okuzumi, Mochimaru, Masaki, Kabata, Chubachi, Arita and Fukunaga.)

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. However, it is still urgent to develop innovative treatments that can effectively manage refractory patients with unpredictable chronic disease courses. In this study, we evaluated the therapeutic efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a novel agent for AD treatment using a human-like mouse model of AD. PLAG significantly improved 2,4-dinitrochlorobenzene (DNCB)-induced AD skin lesions compared to those in mice treated with DNCB alone. PLAG substantially modulated the AD-induced infiltration of monocytes and eosinophils into skin lesions and humoral systemic responses involving immunoglobulin E (IgE), interleukin (IL)-4, and IL-13, restoring them to a normal state. Next, we compared the therapeutic efficacy of PLAG and abrocitinib for severe AD treatment. PLAG exhibited a significant therapeutic effect on AD skin lesions compared to abrocitinib. Unlike abrocitinib, PLAG significantly reduced AD-induced eosinophil infiltration to a level similar to that observed in untreated negative controls. Notably, both PLAG and abrocitinib downregulated IgE, IL-4, and IL-13 in a similar pattern, reaching levels similar to those in the untreated negative controls. Our findings strongly suggest that PLAG may serve as a therapeutic agent for AD with an efficacy comparable to that of abrocitinib., (© 2024. The Author(s).)

The role of eosinophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains ambiguous and likely differs from its role in asthma. The molecular processes underlying the differences between eosinophils from asthma and COPD have not been sufficiently studied. The objective of this study was to compare the transcriptomic profiles of blood eosinophils in COPD and asthma. Eosinophils were isolated from peripheral blood drawn from stable mild-to-moderate COPD and asthma patients. RNA was isolated from eosinophils and sequenced using an NGSelect RNA. The prepared libraries were sequenced on an Illumina platform. The study group included five patients with asthma and four patients with COPD. The RNA-Seq data analysis identified 26 differentially expressed genes between COPD and asthma (according to adjusted p-value). In total, 6 genes were upregulated (e.g. CCL3L1, CCL4L2, GPR82) and 20 were downregulated (e.g. JUN, IFITM3, DUSP1, GNG7) in peripheral eosinophils of COPD patients compared to asthma. The genes associated with signalling of IL-4 and IL-13 pathways were downregulated in COPD eosinophils compared to asthma. In conclusion, blood eosinophils from COPD and asthma patients present different transcriptomic profiles suggesting their different function in pathobiology of both obstructive airway diseases. These differences might indicate the direction of the search of targeted therapy in COPD., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation., (© 2024 GSK and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The role of eosinophils in airway inflammation and asthma pathogenesis is well established, with raised eosinophil counts in blood and sputum associated with increased disease severity and risk of asthma exacerbation. Conversely, there is also preliminary evidence suggesting antiviral properties of eosinophils in the airways. These dual roles for eosinophils are particularly pertinent as respiratory virus infections contribute to asthma exacerbations. Biologic therapies targeting key molecules implicated in eosinophil-associated pathologies have been approved in patients with severe asthma and, therefore, the effects of depleting eosinophils in a clinical setting are of considerable interest. This review discusses the pathological and antiviral roles of eosinophils in asthma and exacerbations. We also highlight the significant reduction in asthma exacerbations seen with biologic therapies, even at the height of the respiratory virus season. Furthermore, we discuss the implications of these findings in relation to the role of eosinophils in inflammation and antiviral responses to respiratory virus infection in asthma., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Altered biosynthesis of eicosanoids is linked to type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), but their role in recalcitrant NPs is unclear., Objectives: We sought to identify endotypes that are linked to recalcitrant CRSwNP, based on eicosanoids, their biosynthetic enzymes, and receptors as well as cytokines and the presence of eosinophils and mast cells in recurrent NPs., Methods: Mucosal tissue collected at the time of sinus surgery from 54 patients with CRSwNP and 12 non-CRS controls were analysed for leukotriene (LT) E4, prostaglandin (PG) D2, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 17 cytokines with ELISAs and Bio-Plex immunoassays. Patient subgroups were identified by cluster analysis and the probability of NP recurrence were tested with logistic regression analyses. Gene expressions were analysed with qPCR. Tryptase and eosinophil-derived neurotoxin (EDN) were measured with ELISAs as indications of the presence of mast cells and eosinophils, respectively., Results: Clustering of patients showed that an inflammatory signature characterised by elevated LTE 4 , PGD 2 , 15(S)-HETE and IL-13 was associated with NP recurrence. Previous NP surgery as well as aspirin-exacerbated respiratory disease were significantly more common among these patients. Expression of cyclooxygenase 1 was the only gene associated with NP recurrence. Levels of EDN, but not tryptase, were significantly higher in patients with recurrent NPs., Conclusion: Distinguishing endotypes that include LTE 4 , PGD 2 , 15HETE and conventional biomarkers of type 2 inflammation could help predict recurrent nasal polyposis and thus identify cases of recalcitrant CRSwNP., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Improvement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy., Methods: A cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy., Results: The Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4 + T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4 + T cells in the airways, and mitigated airway Th2 polarization., Conclusions: We constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4 + T cell apoptosis, and reconcile airway Th2 polarization., (© 2024. The Author(s).)

Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if estrogens affect eosinophil biology in tumors and how this influences ICB efficacy has not been determined. Here, we report that estrogens decrease the number of peripheral eosinophils and TATE, and this contributes to increased tumor growth in validated murine models of breast cancer and melanoma. Moreover, estrogen signaling in healthy female mice also suppressed peripheral eosinophil prevalence by decreasing the proliferation and survival of maturing eosinophils. Inhibiting estrogen receptor (ER) signaling decreased tumor growth in an eosinophil-dependent manner. Further, the efficacy of ICBs was increased when administered in combination with anti-estrogens. These findings highlight the importance of ER signaling as a regulator of eosinophil biology and TATE and highlight the potential near-term clinical application of ER modulators to increase ICB efficacy in multiple tumor types.

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, but not Piezo2 expression, in these cells, confirming the presence of the Piezo1 protein. Activation of Piezo1 with Yoda1, its specific agonist, resulted in a significant calcium influx, which was inhibited by the Piezo1-specific inhibitor Dooku1, as well as other nonspecific inhibitors (Ruthenium Red, Gd 3+ , and GsMTx-4). Further analysis revealed that Piezo1 activation modulated the expression and secretion of both pro-inflammatory and anti-inflammatory cytokines in AML14.3D10 cells. Notably, supernatants from Piezo1-activated AML14.3D10 cells enhanced capsaicin and ATP-induced calcium responses in the dorsal root ganglion neurons of mice. These findings elucidate the physiological role of Piezo1 in AML14.3D10 cells and suggest that factors secreted by these cells can modulate the activity of transient receptor potential 1 (TRPV1) and purinergic receptors, which are associated with pain and itch signaling. The results of this study significantly advance our understanding of the function of Piezo1 channels in the immune and sensory nervous systems.

SARS-CoV-2 caused the pandemic situation experienced since the beginning of 2020, and many countries faced the rapid spread and severe form of the disease. Mechanisms of interaction between the virus and the host were observed during acute phase, but few data are available when related to immunity dynamics in convalescents. We conducted a longitudinal study, with 51 healthy donors and 62 COVID-19 convalescent patients, which these had a 2-month follow-up after symptoms recovery. Venous blood sample was obtained from all participants to measure blood count, subpopulations of monocytes, lymphocytes, natural killer cells and dendritic cells. Serum was used to measure cytokines, chemokines, growth factors, anti-N IgG and anti-S IgG/IgM antibodies. Statistic was performed by Kruskal-Wallis test, and linear regression with days post symptoms and antibody titers. All analysis had confidence interval of 95%. Less than 35% of convalescents were anti-S IgM+, while more than 80% were IgG+ in D30. Anti-N IgG decreased along time, with loss of seroreactivity of 13%. Eosinophil count played a distinct role on both antibodies during all study, and the convalescence was orchestrated by higher neutrophil-to-lymphocyte ratio and IL-15, but initial stages were marked by increase in myeloid DCs, B1 lymphocytes, inflammatory and patrolling monocytes, G-CSF and IL-2. Later convalescence seemed to change to cytotoxicity mediated by T lymphocytes, plasmacytoid DCs, VEGF, IL-9 and CXCL10. Anti-S IgG antibodies showed the longest perseverance and may be a better option for diagnosis. The inflammatory pattern is yet present on initial stage of convalescence, but quickly shifts to a reparative dynamic. Meanwhile eosinophils seem to play a role on anti-N levels in convalescence, although may not be the major causative agent. We must highlight the importance of immunological markers on acute clinical outcomes, but their comprehension to potentialize adaptive system must be explored to improve immunizations and further preventive policies., (© 2024. The Author(s).)

Background: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear., Objectives: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU., Methods: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils., Results: Our CSU patients had markedly increased rates of circulating Gal-9 + eosinophils and basophils and high numbers of lesional Gal-9 + cells. High rates of blood Gal-9 + eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9 + eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9 + eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9 + eosinophils/basophils in responders. Gal-9 + eosinophils/basophils were negatively correlated with TIM-3 + T H 17 cells., Conclusion: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Flow cytometry has been widely used to study immunophenotypic patterns of maturation of most hematopoietic lineages in normal human bone marrow aspirates, thus allowing identification of changes in patterns in many myeloid malignancies. Eosinophils play an important role in a wide variety of disorders, including some myeloid neoplasms. However, changes in flow cytometric immunophenotypic patterns during normal and abnormal bone marrow eosinophilopoiesis have not been well studied., Methods: Fresh bone marrow aspirates from 15 healthy donors, 19 patients with hypereosinophilic syndromes (HES), and 11 patients with systemic mastocytosis (SM) were analyzed for candidate markers that included EMR-1, Siglec-8, CCR3, CD9, CD11a, CD11b, CD11c, CD13, CD16, CD29, CD34, CD38, CD45, CD44, CD49d, CD49f, CD54, CD62L, CD69, CD117, CD125 (IL-5Rα), HLA-DR, using 10 parameter flow cytometry. Putative CD34-negative immature and mature normal eosinophil populations were first identified based on changes in expression of the above markers in healthy donors, then confirmed using fluorescence-based cell sorting and morphological evaluation of cytospin preparations. The normal immunophenotypic patterns were then compared to immunophenotypic patterns of eosinophilopoiesis in patients with HES and SM., Results: The eosinophilic lineage was first verified using the human eosinophil-specific antibody EMR-1 in combination with anti-IL-5Rα antibody. Then, a combination of Siglec-8, CD9, CD11b, CCR3, CD49d, and CD49f antibodies was used to delineate normal eosinophilic maturational patterns. Early stages (eosinophilic promyelocytes/myelocytes) were identified as Siglec-8 dim/CD11b dim to moderate/CD9 dim/CCR3 dim/CD49d bright/CD49f dim, intermediate stages (eosinophilic myelocytes/metamyelocytes) as Siglec-8 moderate/CD11b moderate to bright/CD9 moderate/CCR3 moderate/CD49d moderate/CD49f moderate and mature bands/segmented eosinophils as Siglec-8 bright/CD11b bright/CD9 bright/CCR3 bright/CD49d dim/CD49f bright. Overall maturational patterns were also similar in patients with HES and SM; however, the expression levels of several surface markers were altered compared to normal eosinophils., Conclusion: A novel flow cytometric antibody panel was devised to detect alterations in immunophenotypic patterns of bone marrow eosinophil maturation and evaluated in normal, HES and SM samples. This approach will allow us to elucidate changes in immunophenotypic patterns of bone marrow eosinophilopoiesis in other hematological diseases., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)

Characterization of inflammation in chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) is an ongoing research process. To overcome limitations of current cytologic techniques, we investigated whether immunofluorescence multiplex image cytometry could quantify intact neutrophils, eosinophils, and other immune cells in solid upper airway mucosa. We used a four-channel immunofluorescence-microscopy technique for the simultaneous detection of the leukocyte marker CD45, the neutrophil marker myeloperoxidase, two eosinophil markers, i.e., major basic protein and eosinophil peroxidase, and DAPI (4',6-diamidin-2-phenylindole), in formalin-fixed paraffin-embedded upper airway tissue samples of patients with CRSwNP and CRSsNP, as well as of patients free of CRS with inferior turbinate hypertrophy (controls). Image acquisition and analysis were performed with TissueFAXS and StrataQuest (TissueGnostics, Vienna, Austria), respectively. Positive and negative immunostaining were differentiated with a specific fluorescence signal/background signal ratio. Isotype controls were used as negative controls. In six controls, nine patients with CRSsNP, and 11 patients with CRSwNP, the median area scanned and median cell count per patient were 14.2 mm 2 and 34,356, respectively. In CRSwNP, the number of eosinophils was three times higher (23%) than that of neutrophils (7%). Three times more immune cells were encountered in CRSwNP (33%) compared to CRSsNP (11%). In controls, inflammation was balanced between the epithelial layer and lamina propria, in contrast to CRS (three times more pronounced inflammation in the lamina propria). The quantification of intact neutrophils, eosinophils, and other immune cells in solid tissue with undisrupted architecture seems feasible with immunofluorescence multiplex image cytometry., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: In recent years, the clinical efficacy of medications for adenoid hypertrophy has been demonstrated. Topical nasal steroids have effects to shrink hypertrophic adenoids and improve symptoms of associated diseases. However, the mechanism which topical steroid administrations cause adenoid shrinkage remains unclear, herein, sensitivity for topical steroids in the mucosal epithelium of adenoids was evaluated histologically by comparing with tonsils., Methods: Histological analysis was performed on adenoids and tonsils removed from 32 pediatric patients with adenoid hypertrophy. In hematoxylin-eosin-stained specimens, the morphology of the mucosal epithelium and eosinophil infiltration were evaluated. The expression of the glucocorticoid receptor (GR), interleukin (IL)-4, and IL-25 in the mucosal epithelium was evaluated, and the staining intensity was scored as 0 (none), 1 (weak), and 2 (strong). The number of eosinophils and expression scores of GR, IL-4, and IL-25 were statistically compared between adenoids and tonsils and analyzed correlations with adenoids sizes., Results: Adenoids were covered with ciliated epithelium, and eosinophils in the mucosal epithelium and submucosal area was higher than tonsils (p < 0.05). GR expression in the most superficial layer of the mucosal epithelium was observed in adenoids, and the expression intensity score was higher than that in tonsils (p < 0.05). IL-4 and IL-25 were more widely expressed in the mucosal epithelium of adenoids than in tonsils, and their expression intensity scores were also higher than in tonsils (p < 0.05). A correlation was found between adenoid size and the intensity of IL-25 expression in the adenoid epithelium (p < 0.05)., Conclusion: Eosinophilic inflammations in adenoids mucosal epithelium could be one of etiology of adenoid hypertrophy, and the GR and eosinophilic inflammation in the adenoids mucosal epithelium might be target of topical nasal steroids to shrink hypertrophic adenoids., Competing Interests: Declaration of competing interest All authors have no financial conflicts of interest disclose concerning this study and article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Achieving disease control is the goal of asthma management. Serum or sputum eosinophil counts have been known traditional means of assessing eosinophilic airway inflammation in asthma, which is vital in predicting response to corticosteroid therapy which ultimately promotes control of the disease. Evidence suggests that fraction of exhaled nitric oxide (FeNO) may be a more useful non-invasive surrogate biomarker for the assessment of eosinophilic airway inflammation and could help with the timely adjustment of inhaled corticosteroid therapy in the uncontrolled asthma patient. The relationship between FeNO and other markers of airway inflammation has been variable in literature, with limited data in sub-Saharan Africa where FeNO testing is very sparse. We sought to define the relationship between FeNO levels, serum eosinophil counts, spirometry measures and symptom control among asthma patients., Materials and Methods: The study was conducted at the Asthma Clinic of a large tertiary hospital. This study included 82 patients with physician-diagnosed asthma being regularly managed at the clinic. All participants were taken through the asthma control test (ACT), had FeNO and spirometry measurements taken according to the American Thoracic Society (ATS) guidelines. Blood samples were obtained from all participants for serum eosinophil counts. Correlation coefficient was used to ascertain the relationship between FeNO levels and serum eosinophil counts, ACT scores, and spirometry measurements. Logistic regression was used to examine the association between high FeNO and abnormal FEV 1 percentage predicted (<80%) with adjustments for age, sex, and BMI., Results: A total of 82 patients with asthma were included in the study, with higher prevalence of females (72%). Majority (40.2%) of the patients were found in the 60 and above age category. The median FeNO level and ACT score was 42.00 (26.00-52.50) parts per billion (ppb) and 20.0 (18-23) respectively. The median serum eosinophil counts was 0.25(0.90-0.38) × 10 9 /L. The median FeNO levels were significantly higher in patients with partly and very poorly controlled asthma than in the well-controlled group ( p  < 0.001). A total of 47(57%) of the patients were classified as having well controlled asthma and 35 (42%) uncontrolled. FeNO correlated with serum eosinophil counts ( r  = 0.450, p  < 0.001), ACT ( r  = -0.648, p  < 0.001), and FEV1 percentage predicted ( r  = -0.353, p  = 0.001). High FeNO (>50 ppb) was associated with an over fivefold increased risk of having an abnormal FEV 1 percentage predicted., Conclusion: FeNO levels significantly correlated with the ACT scores, serum eosinophil counts and FEV1% predicted among the asthma patients who were on inhaled corticosteroid therapy. High FeNO was significantly associated with abnormal FEV 1 percentage predicted. We suggest that the point of care assessment of FeNO is a reliable marker of eosinophilic inflammation in our cohort of patients and together with 'ACT scores' in our asthma clinics could increase asthma control rates.

Eosinophils, traditionally associated with allergic phenomena, play a pivotal role in inflammatory responses. Despite accumulating evidence suggesting their pro-inflammatory function upon activation, the underlying mechanisms governing eosinophil activation remain incompletely characterized. In this study, we investigate the local activation of pulmonary and colon eosinophils within the inflammatory microenvironment. Leveraging transcriptional sequencing, we identify TGF-β as a putative regulator of eosinophil activation, leading to the secretion of granule proteins, including peroxidase. Genetic deletion of TGF-β receptors on eosinophils resulted in the inhibition of peroxidase synthesis, affirming the significance of TGF-β signaling in eosinophil activation. Using models of HDM-induced asthma and DSS-induced colitis, we demonstrate the indispensability of TGF-β-driven eosinophil activation in both disease contexts. Notably, while TGF-β signaling did not significantly influence asthmatic inflammation, its knockout conferred protection against experimental colitis. This study delineates a distinct pattern of eosinophil activation within inflammatory responses, highlighting the pivotal role of TGF-β signaling in regulating eosinophil behavior. These findings deepen our comprehension of eosinophil-related pathophysiology and may pave the way for targeted therapeutic approaches in allergic and inflammatory diseases., (© 2024. The Author(s).)

Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-β (LTβ) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-β receptor (LTβR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor-dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration-approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.

Objective: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair., Design: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf)., Result: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury., Conclusion: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Atopic dermatitis (AD) presents significant therapeutic challenges due to its poorly understood etiology. Eosinophilia, a hallmark of allergic inflammation, is implicated in AD pathogenesis. Interleukin-10 (IL-10)-producing regulatory B (Breg) cells exhibit potent anti-inflammatory effects. However, their role in controlling AD-related eosinophilia is not well understood. To investigate the impact of eosinophils on AD, we employed IL-5Rα-deficient (Il5ra -/- ) mice, which lack functional eosinophils. Induction of AD in these mice resulted in attenuated disease symptoms, underscoring the critical role of eosinophils in AD development. Additionally, the adoptive transfer of purified Breg cells into mice with AD significantly alleviated disease severity. Mechanistic studies revealed that IL-10 produced by Breg cells directly inhibits eosinophil activation and infiltration into the skin. In vitro experiments further confirmed that Breg cells inhibited eosinophil peroxidase secretion in an IL-10-dependent manner. Our collective findings demonstrate that IL-10 from Breg cells alleviates AD by suppressing eosinophil activation and tissue infiltration. This study elucidates a novel regulatory mechanism of Breg cells, providing a foundation for future Breg-mediated therapeutic strategies for AD., (© 2024. The Author(s).)

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are chronic inflammatory disorders of the gastrointestinal tract, with EoE predominantly provoked by food and aeroallergens, whereas IBD is driven by a broader spectrum of immunopathological and environmental triggers. This review presents a comprehensive comparison of the pathophysiological and therapeutic strategies for EoE and IBD. We examine the current understanding of their underlying mechanisms, particularly the interplay between environmental factors and genetic susceptibility. A crucial element in both diseases is the integrity of the epithelial barrier, whose disruption plays a central role in their pathogenesis. The involvement of eosinophils, mast cells, B cells, T cells, dendritic cells, macrophages, and their associated cytokines is examined, highlighting the importance of targeting cytokine signaling pathways to modulate immune-epithelial interactions. We propose that advances in computation tools will uncover the significance of G-protein coupled receptors (GPCRs) in connecting immune and epithelial cells, leading to novel therapies for EoE and IBD.

The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year's exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation., Competing Interests: The authors declare no conflicts of interest.

Background: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma., Methods: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways., Results: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-β1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced., Conclusion: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Eosinophils are key effector cells mediating airway inflammation and exacerbation in patients with severe eosinophilic asthma. They are present in increased numbers and activation states in the airway mucosa and lumen. Interleukin-5 (IL-5) is the key eosinophil growth factor that is thought to play a role in eosinophil priming and activation. However, the mechanism of these effects is still not fully understood. The anti-IL-5 antibody mepolizumab reduces eosinophil counts in the airway modestly but has a large beneficial effect on the frequency of exacerbations of severe eosinophilic asthma, suggesting that reduction in eosinophil priming and activation is of central mechanistic importance. In this study, we used the therapeutic effect of mepolizumab and single-cell ribonucleic acid sequencing to investigate the mechanism of eosinophil priming and activation by IL-5. We demonstrated that IL-5 is a dominant driver of eosinophil priming and plays multifaceted roles in eosinophil function. It enhances eosinophil responses to other stimulators of migration, survival, and activation by activating phosphatidylinositol-3-kinases, extracellular signal-regulated kinases, and p38 mitogen-activated protein kinases signaling pathways. It also enhances the pro-fibrotic roles of eosinophils in airway remodeling via transforming growth factor-β pathway. These findings provide a mechanistic understanding of eosinophil priming in severe eosinophilic asthma and the therapeutic effect of anti-IL-5 approaches in the disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen. NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.

Extracellular traps (ETs) are a specialized form of innate immune defense in which leukocytes release ETs composed of chromatin and active proteins to eliminate pathogenic microorganisms. In addition to the anti-infection effect of ETs, researchers have also discovered their involvement in the pathogenesis of inflammatory disease, tumors, autoimmune disease, and allergic disease. Asthma is a chronic airway inflammatory disease involving multiple immune cells. The increased level of ETs in asthma patients suggests that ETs play an important role in the pathogenesis of asthma. Here we review the research work on the formation mechanism, roles, and therapeutic strategies of ETs released by neutrophils, eosinophils, and macrophages in asthma., (© 2024. The Author(s).)

Immune cell-derived extracellular vesicles (EV) affect tumor progression and hold promise for therapeutic applications. Eosinophils are major effectors in Th2-related pathologies recently implied in cancer. Here, we evaluated the anti-tumor activities of eosinophil-derived EV following activation with the alarmin IL-33. We demonstrate that IL-33-activated mouse and human eosinophils produce higher quantities of EV with respect to eosinophils stimulated with IL-5. Following incorporation of EV from IL-33-activated eosinophils (Eo33-EV), but not EV from IL-5-treated eosinophils (Eo5-EV), mouse and human tumor cells increased the expression of cyclin-dependent kinase inhibitor (CDKI)-related genes resulting in cell cycle arrest in G0/G1, reduced proliferation and inhibited tumor spheroid formation. Moreover, tumor cells incorporating Eo33-EV acquired an epithelial-like phenotype characterized by E-Cadherin up-regulation, N-Cadherin downregulation, reduced cell elongation and migratory extent in vitro, and impaired capacity to metastasize to lungs when injected in syngeneic mice. RNA sequencing revealed distinct mRNA signatures in Eo33-EV and Eo5-EV with increased presence of tumor suppressor genes and enrichment in pathways related to epithelial phenotypes and negative regulation of cellular processes in Eo33-EV compared to Eo5-EV. Our studies underscore novel IL-33-stimulated anticancer activities of eosinophils through EV-mediated reprogramming of tumor cells opening perspectives on the use of eosinophil-derived EV in cancer therapy., (© 2024. The Author(s).)

Eosinophil-mediated pathophysiology is tissue destructive and tissue altering with proinflammatory, prothrombotic, and profibrotic effects. The distinctive morphology of an eosinophil reveals a cytoplasm chockfull of unique granules, and the granule proteins have numerous toxic effects on cells, tissues, and organs. Eosinophils are not found in most human tissues, and eosinophil involvement in diseased tissues generally is identified by cell infiltration on histopathologic examination. However, eosinophils characteristically lose their structural integrity and deposit granules and granule proteins at sites of inflammation. Hence, their participation in tissue damage may be underrecognized or entirely overlooked. The eosinophil major basic protein 1 is a toxic granule protein and, when deposited, persists in tissues. Major basic protein 1 deposition can be regarded as a footprint of eosinophil activity. Analyses of numerous eosinophil-related diseases have demonstrated clear-cut evidence of major basic protein 1 deposition in affected tissues where eosinophils were not recognized by hematoxylin and eosin tissue staining and light microscopy. Eosinophil granule protein deposition, as exemplified by localization of major basic protein 1, especially when disproportionately greater than cellular infiltration, emerges as a biomarker of hidden eosinophil-related pathophysiology. Consequently, current assessments of recognized eosinophils may vastly underestimate their role in disease., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Eosinophils have been mainly studied in allergic diseases and parasitic infections. Nonetheless, eosinophils accumulate in a variety of solid tumors, including colorectal cancer, where their presence is associated with improved prognosis. Eosinophils can promote antitumor immunity through various mechanisms, including direct cytotoxicity toward tumor cells and promoting T-cell activation. However, the mechanisms by which tumor cells regulate eosinophil activities are largely unknown. Herein, we characterized the potential interactions between eosinophils and colorectal cancer cells using an unbiased transcriptomic and proteomic analyses approach. Human eosinophils were stimulated with colorectal cancer cell conditioned media, containing tumor cell secreted factors from multiple cancer cell lines. RNA sequencing analysis identified a "core" signature consisting of 101 genes that characterize a baseline transcriptional program for the response of human eosinophils to colorectal cancer cells. Among these, the increased expression of IL-3Rα and its βc chain was identified and validated at the protein level. Secreted factors from tumor cells potentiated IL-3-induced expression of the adhesion molecule CD11a in eosinophils. Combining proteomics analysis of tumor cell secreted factors with RNA sequencing revealed potential ligand-receptor pairs between tumor cells and eosinophils and the potential involvement of the adhesion molecule CD18 and F2RL3/PAR4. Subsequent functional analyses demonstrated that F2RL3/PAR4 suppresses eosinophil migration in response tumor cell secreted factors. These findings add to the growing body of evidence that eosinophils are conditioned by their local microenvironment. Identifying mechanisms by which eosinophils interact with tumor cells could lead to the development of new immunotherapies for colorectal cancer and other solid tumors., Competing Interests: Conflict of interest statement. Ariel Munitz serves on international advisory boards for GlaxoSmithKline, AstraZeneca, and Oravax and received honorariums from Sanofi. Other authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Eosinophils, recognized for their immune and remodeling functions and participation in allergic inflammation, have recently garnered attention due to their impact on host metabolism, especially in the regulation of adipose tissue. Eosinophils are now known for their role in adipocyte beiging, adipokine secretion, and adipose tissue inflammation. This intricate interaction involves complex immune and metabolic processes, carrying significant implications for systemic metabolic health. Importantly, the interplay between eosinophils and adipocytes is bidirectional, revealing the dynamic nature of the immune-metabolic axis in adipose tissue. While the homeostatic regulatory role of eosinophils in adipose tissue is appreciated, this relationship in the context of obesity or allergic inflammation is much less understood. Mechanistic details of eosinophil-adipose interactions, especially the direct regulation of adipocytes by eosinophils, are also lacking. Another poorly understood aspect is the metabolism of the eosinophils themselves, encompassing metabolic shifts during eosinophil subset transitions in different tissue microenvironments, along with potential effects of host metabolism on the programming of eosinophil hematopoiesis and the resulting plasticity. This review consolidates recent research in this emerging and fascinating frontier of eosinophil investigation, identifying unexplored areas and presenting innovative perspectives on eosinophil biology in the context of metabolic disorders and associated health conditions, including asthma., Competing Interests: Conflict of interest statement. All authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Eosinophils are leukocytes characterized by their ability to release granule content that is highly rich in enzymes and proteins. Besides the antihelminthic, bactericidal, and antiviral properties of eosinophils and their secretory granules, these also play a prominent role in the pathophysiology of diseases such as asthma, eosinophilic esophagitis, and other hypereosinophilic conditions by causing tissue damage and airway hyperresponsiveness. Although this cell was first recognized mainly for its capacity to release granule content, nowadays other capabilities such as cytokine secretion have been linked to its physiology, and research has found that eosinophils are not only involved in innate immunity, but also as orchestrators of immune responses. Nearly 10 yr ago, eosinophil-derived extracellular vesicles (EVs) were first described; since then, the EV field has grown exponentially, revealing their vital roles in intracellular communication. In this review, we synthesize current knowledge on eosinophil-derived EVs, beginning with a description of what they are and what makes them important regulators of disease, followed by an account of the methodologies used to isolate and characterize EVs. We also summarize current understanding of eosinophil-derived vesicles functionality, especially in asthma, the disease in which eosinophil-derived EVs have been most widely studied, describing how they modulate the role of eosinophils themselves (through autocrine signaling) and the way they affect airway structural cells and airway remodeling. Deeper understanding of this cell type could lead to novel research in eosinophil biology, its role in other diseases, and possible use of eosinophil-derived EVs as therapeutic targets., Competing Interests: Conflict of interest statement. J.M.R.-M. reports receiving payments for lectures and educational events from AstraZeneca and GSK. V.d.P. has received honoraria (advisory board, speaker) and/or institutional grant/research support from AstraZeneca and GSK and unpaid Leadership or fiduciary role in committees of the EAACI. All other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Asthma affects 25 million Americans, and recent advances in treatment are effective for only a portion of severe asthma patients. TREM-1, an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. It is unknown how TREM-1 contributes to allergic asthma pathology. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow-derived eosinophils by incubation with interleukin 33, lipopolysaccharide, or granulocyte-macrophage colony-stimulating factor. Compared to TREM-1- airway eosinophils, TREM-1+ eosinophils were enriched for proinflammatory gene sets, including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 exacerbated airway interleukin (IL) 5 production, airway MUC5AC production, and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis and superoxide generation-related gene sets were enriched in TREM-1+ eosinophils. Consistent with these findings, annexin V and caspase-3/7 staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1- eosinophils in the inflammatory airway. In vitro, Trem1/3-/- bone marrow-derived eosinophils consumed less oxygen than wild-type in response to phorbol myristate acetate, suggesting that TREM-1 promotes superoxide generation in eosinophils. These data reveal protein-level expression of TREM-1 by eosinophils, define a population of TREM-1+ inflammatory eosinophils, and demonstrate that eosinophil TREM-1 restricts key features of type 2 lung inflammation., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Eosinophils not only function as inflammatory effectors in allergic diseases, but also contribute to tissue homeostasis in steady state. Emerging data are revealing tissue eosinophils to be adaptive cells, imprinted by their local tissue microenvironment and exhibiting distinct functional phenotypes that may contribute to their homeostatic vs. inflammatory capacities. However, signaling pathways that regulate eosinophil tissue adaptations remain elusive. Notch signaling is an evolutionarily conserved pathway that mediates differential cell fate programming of both pre- and postmitotic immune cells. This study investigated a role for notch receptor 2 signaling in regulating eosinophil functions and tissue phenotype in both humans and mice. Notch 2 receptors were constitutively expressed and active in human blood eosinophils. Pharmacologic neutralization of notch 2 in ex vivo stimulated human eosinophils altered their activated transcriptome and prevented their cytokine-mediated survival. Genetic ablation of eosinophil-expressed notch 2 in mice diminished steady-state intestine-specific eosinophil adaptations and impaired their tissue retention in a food allergic response. In contrast, notch 2 had no effect on eosinophil phenotype or tissue inflammation within the context of allergic airways inflammation, suggesting that notch 2-dependent regulation of eosinophil phenotype and function is specific to the gut. These data reveal notch 2 signaling as a cell-intrinsic mechanism that contributes to eosinophil survival, function, and intestine-specific adaptations. The notch 2 pathway may represent a viable strategy to reprogram eosinophil functional phenotypes in gastrointestinal eosinophil-associated diseases., Competing Interests: Conflict of interest The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Intestinal eosinophils express the aryl hydrocarbon receptor (AHR), an environmental sensor and ligand-activated transcription factor that responds to dietary or environmental ligands. AHR regulates tissue adaptation, survival, adhesion, and immune functions in intestinal eosinophils. The AHR repressor (AHRR) is itself induced by AHR and believed to limit AHR activity in a negative feedback loop. We analyzed gene expression in intestinal eosinophils from wild-type and AHRR knockout mice and found that AHRR did not suppress most AHR-dependent genes. Instead, AHRR limited the expression of a distinct small set of genes involved in the innate immune response. These included S100 proteins, antimicrobial proteins, and alpha-defensins. Using bone marrow-derived eosinophils, we found that AHRR knockout eosinophils released more reactive oxygen species upon stimulation. This work shows that the paradigm of AHRR as a repressor of AHR transcriptional activity does not apply to intestinal eosinophils. Rather, AHRR limits the expression of innate immune response and antimicrobial genes, possibly to maintain an anti-inflammatory phenotype in eosinophils when exposed to microbial signals in the intestinal environment., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Eosinophils are important immune effector cells that affect T cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1 O 2 -cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1 O 2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy., (© 2024 Wiley-VCH GmbH.)

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Eosinophils account for a significant portion of immune cells in the body. It is well known that eosinophils play a role in the pathogenesis of many diseases. In which the interaction between eosinophils and other immune cells is incompletely understood. The aim of this study is to characterize the immune suppressive functions of eosinophils. In this study, an irway allergy mouse model was established. Eosinophils were isolated from the airway tissues using flow cytometry cell sorting. The RAW264.7 cell line was used to test the immune suppressive functions of eosinophils. We observed that eosinophils had immune suppressive functions manifesting inhibiting immune cell proliferation and cytokine release from other immune cells. The eosinophil's immune suppressive functions were mediated by eosinophil-derived molecules, such as eosinophil peroxidase (EPX) and major basic protein (MBP). The expression of Ras-like protein in the brain 27a (Rab27a) was detected in eosinophils, which controlled the release of MBP and EPX by eosinophils. Eosinophil mediators had two contrast effects on inducing inflammatory responses or rendering immune suppressive effects, depending on the released amounts. Administration of an inhibitor of Rab27a at proper dosage could alleviate experimental airway allergy. To sum up, eosinophils have immune suppressive functions and are also inflammation inducers. Rab27a governs the release of EPX and MBP from eosinophils, which leads to immune suppression or inflammation. Modulation of Rab27a can alleviate airway allergy responses by modulating eosinophil's immune suppressive functions, which has the translational potential for the management of eosinophil-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA + eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Asthma is a common disease, and among the most predominant causes of the years lived with disability. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising avenue for asthma management. The objective of this study is to perform a systematic review and meta-analysis of pre-clinical studies investigating the therapeutic use of MSC-EVs in murine models of asthma., Methods: A systematic search of electronic databases was performed. Meta-analyses were conducted on broncho-alveolar lavage fluid (BALF) cells and cytokines, as well as airway hyper-responsiveness Penh values and histological staining scores to determine the efficacy of MSC-EVs-based therapy, comparing treated rodents with untreated ones. BALF IL-4, BALF total cells, and BALF eosinophils were chosen as the primary outcomes, while airway hyper-responsiveness Penh values, BALF cytokines excluding IL-4, and histological staining scores were chosen as secondary outcomes., Results: A total of 19 eligible studies were included in the current systematic review, with 9 assessing BALF IL-4, 11 assessing BALF total cells, and 10 assessing BALF eosinophils. Pooled Hedges' g (p-value) for each outcome was - 4.407 (< 0.001), -4.976 (< 0.001), and - 4.071 (< 0.001), showing that MSC-EVs therapy inhibits asthma pathology. Changes in secondary outcomes also indicated a reduction in inflammation, goblet cell hyperplasia, and airway hyper-responsiveness. Subgroup analyses did not reveal significant disparities between the type of rodents and administration routes, and meta-regressions were only significant for MSC-EVs source and dose in the IL-4 meta-analysis, and for administration frequency and time from the last challenge to sacrifice in the BALF total cell meta-analysis., Conclusion: This review highlights the current pre-clinical evidence of MSC-EVs therapy for asthma and finds its application ameliorates multiple aspects of asthma's pathology. We further underline the importance of MSC-EVs source, dose, administration frequency, and timing on the therapeutic effect and warrant further investigation and clinical translation to assess the best treatment regimen and to gauge the efficacy of EV therapy in human asthma cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The phenotyping of chronic obstructive pulmonary disease (COPD) has increasingly gained attention in recent years, as it leads to new and individualized therapeutic concepts., Objective: The aim is to provide an overview of the heterogeneity of COPD and to summarize current drug therapy concepts, particularly in the context of eosinophilic airway inflammation., Data: Several prospective, randomized, placebo-controlled studies have shown a reduction in exacerbations and overall mortality with inhaled triple therapy using an inhaled corticosteroid and dual bronchodilation. The higher the eosinophils in the blood, the greater the expected effect. In addition, a reduction in exacerbations with biologics in COPD with eosinophilia has been demonstrated for dupilumab. Eosinophil-guided therapy for acute exacerbations is the subject of current research., Conclusion: For COPD without exacerbations, dual bronchodilation forms the basis of inhaled therapy. With exacerbations, inhaled triple therapy is indicated for patients with a blood eosinophil count of ≥ 300/µl. This type of treatment may also be useful when eosinophils are between 100 and 300/µl. Therapy with dupilumab is a possible option for the eosinophilic phenotype in the near future., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)