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Background: Psychological stress can exacerbate the development of allergies; however, the underlying mechanisms remain poorly understood. IgE-mediated cutaneous allergic inflammation (IgE-CAI) is a basophil-dependent skin allergy with eosinophil infiltration at inflammatory sites. Its resolution involves anti-inflammatory programmed death ligand 2 (PD-L2) + macrophages., Objective: This study sought to elucidate the cellular and molecular mechanisms by which psychological stress exacerbates IgE-CAI., Methods: Neural tissue involved in stress-induced IgE-CAI exacerbation was identified by performing denervation and brain destruction experiments in mice. Immune cell transplantation, RNA sequencing, flow cytometry, and ELISA were used to identify and characterize immune cells with stress-altered functioning, followed by identification of key factors involved in IgE-CAI exacerbation., Results: Stress-induced exacerbation of IgE-CAI was found to be sympathetic and β2-adrenergic receptor (Adrb2)-dependent. Adoptive transfer experiments revealed that stress diminished the anti-inflammatory functions of PD-L2 + macrophages through Adrb2, exacerbating the inflammation. RNA sequencing analysis indicated that PD-L2 + macrophages in stressed mice exhibit reduced expression of efferocytosis-related genes, including Gas6 and MerTK. Consequently, the efferocytic capacity of these macrophages decreased, resulting in increased numbers of dead cells in the lesions. The exacerbation and upregulation of Ccl24 expression in IgE-CAI skin lesions were countered by a caspase-1 inhibitor., Conclusions: Psychological stress diminishes the efferocytotic capacity of PD-L2 + macrophages, causing an accumulation of dead cells. This, in turn, heightens eosinophil infiltration through caspase-1-dependent production of Ccl24, exacerbating IgE-CAI., (Copyright © 2024. Published by Elsevier Inc.)

Background: Basophils, despite being the least common granulocytes, play crucial roles in type 2 immune responses, such as chronic allergic inflammation and protective immunity against parasites. However, the molecular mechanisms regulating basophil activation and inflammatory molecule production remain poorly understood. Therefore, we investigated the role of RNA-binding proteins, specifically tristetraprolin (TTP), in regulating inflammatory molecule production in basophils., Methods: Using antigen/IgE-stimulated basophils from wild-type (WT) and TTP-knockout (TTP-KO) mice, we performed bulk RNA sequencing, transcriptome-wide mRNA stability assays, and protein analyses. We also examined mRNA expression and protein production of inflammatory molecules in TTP-KO basophils under stimulation with IL-33 or LPS. Furthermore, we evaluated the in vivo significance of TTP in basophils using basophil-specific TTP-deficient mice and a hapten oxazolone-induced atopic dermatitis model., Results: TTP expression was upregulated in basophils following stimulation with antigen/IgE, IL-33, or LPS. Under these stimuli, TTP-KO basophils exhibited elevated mRNA expression of inflammatory molecules, such as Il4, Areg, Ccl3, and Cxcl2, compared to WT basophils. Transcriptome-wide mRNA stability assays revealed that TTP deficiency prolonged the mRNA half-life of these inflammatory mediators. Notably, the production of these inflammatory proteins was significantly increased in TTP-KO basophils. Moreover, basophil-specific TTP-deficient mice showed exacerbated oxazolone-induced atopic dermatitis-like skin allergic inflammation., Conclusions: TTP is a key regulator of basophil activation, controlling the production of inflammatory mediators through mRNA destabilization. Our in vivo findings demonstrate that the absence of TTP in basophils significantly aggravates allergic skin inflammation, highlighting its potential as a therapeutic target for allergic diseases., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2024 Japanese Society of Allergology. All rights reserved.)

Physical trauma disrupts skin barrier function. How the skin barrier recovers is not fully understood. We evaluated in mice the mechanism of skin barrier recovery after mechanical injury inflicted by tape stripping. Tape stripping disrupted skin barrier function as evidenced by increased transepidermal water loss. We show that tape stripping induces IL-1-, IL-23-, and TCRγδ + -dependent upregulation of cutaneous Il17a and Il22 expression. We demonstrate that IL-17A and IL-22 induce epidermal hyperplasia, promote neutrophil recruitment, and delay skin barrier function recovery. Neutrophil depletion improved the recovery of skin barrier function and decreased epidermal hyperplasia. Single-cell RNA sequencing and flow cytometry analysis of skin cells revealed basophil infiltration into tape-stripped skin. Basophil depletion upregulated Il17a expression, increased neutrophil infiltration, and delayed skin barrier recovery. Comparative analysis of genes differentially expressed in tape-stripped skin of basophil-depleted mice and Il17a -/- mice indicated that basophils counteract the effects of IL-17A on the expression of epidermal and lipid metabolism genes important for skin barrier integrity. Our results demonstrate that basophils play a protective role by downregulating Il17a expression after mechanical skin injury, thereby counteracting the adverse effect of IL-17A on skin barrier function recovery, and suggest interventions to accelerate this recovery., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis is characterized by scratching and a T H 2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells., Objective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T H 2 response to cutaneously encountered antigen and allergic skin inflammation., Methods: DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4 + T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA., Results: Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive T H 2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4 -/- mice and CD11c-CreIl4r flox/- mice, which lack IL-4Rα expression in DCs (DC Δ/Δll4ra mice), were impaired in their capacity to drive T H 2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC Δ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T H 2 response evidenced by reduced T H 2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls., Conclusions: Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for T H 2 polarization and drive allergic skin inflammation., Competing Interests: Disclosure statement The study was supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant no. U19AI117673 to R.S.G. and grant no. R01AI158811 to D.R.W.) and a grant from the Food Allergy Science Initiative (to D.R.W.). J.M.L.C. was supported by CONACYT, Mexico, Boston Children’s Hospital OFD/BTREC/CTREC Faculty Career Development Fellowship, National Institute of Allergy and Infectious Diseases T32 training grant (grant no. 5T32AI007512-32), Dermatology Foundation Research Career Development Award, and National Eczema Association grants; received support from Harvard Catalyst, The Harvard Clinical and Translational Science Center, National Center for Research Resources, and the National Center for Advancing Translational Sciences, National Institutes of Health (award no. UL1 TR002541); and received financial contributions from Harvard University and its affiliated academic health care centers. Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support grant (grant no. NIH 5 P30 CA06516). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Basophils are the least common granulocytes, accounting for <1% of peripheral blood leukocytes. In the last 20 years, analytical tools for mouse basophils have been developed, and we now recognize that basophils play critical roles in various immune reactions, including the development of allergic inflammation and protective immunity against parasites. Moreover, the combined use of flow cytometric analyses and knockout mice has uncovered several progenitor cells committed to basophils in mice. Recently, advancements in single-cell RNA sequencing (scRNA-seq) technologies have challenged the classical view of the differentiation of various hematopoietic cell lineages. This is also true for basophil differentiation, and studies using scRNA-seq analysis have provided novel insights into basophil differentiation, including the association of basophil differentiation with that of erythrocyte/megakaryocyte and the discovery of novel basophil progenitor cells in the mouse bone marrow. In this review, we summarize the recent findings of basophil ontogeny in both mice and humans, mainly focusing on studies using scRNA-seq analyses., 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 authors declared that they were an editorial board member of Frontiers, at the time of submission., (© 2024 Miyake, Ito and Karasuyama.)

Phosphodiesterase 4 inhibitors have been approved for the treatment of atopic dermatitis. However, the cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. In this study, we addressed this unsolved issue by analyzing the action of difamilast, a novel phosphodiesterase 4 inhibitor, on an oxazolone-induced skin allergic inflammation commonly used as a mouse model of atopic dermatitis. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4 expression even when the treatment commenced 4 days after the initiation of oxazolone challenge, showing its therapeutic effect on atopic dermatitis. IL-4-deficient mice displayed milder skin inflammation than did wild-type mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act on basophils. Notably, basophils accumulating in the skin lesion showed highly upregulated expression of Pde4b encoding the B subtype of the phosphodiesterase 4 family. Difamilast suppressed IL-4 production from basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate atopic dermatitis inflammation through the suppression of basophil IL-4 production in the skin lesion., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis., Objective: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation., Methods: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR., Results: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4 + T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic T H 2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive T H 2 polarization of naive T cells., Conclusion: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis., (© 2024. The Author(s).)

Both monocytes and macrophages are heterogeneous populations. It was traditionally understood that Ly6C hi classical (inflammatory) monocytes differentiate into pro-inflammatory Ly6C hi macrophages. Accumulating evidence has suggested that Ly6C hi classical monocytes can also differentiate into Ly6C lo pro-resolving macrophages under certain conditions, while their differentiation trajectory remains to be fully elucidated. The present study with scRNA-seq and flow cytometric analyses reveals that Ly6C hi PD-L2 lo classical monocytes recruited to the allergic skin lesion sequentially differentiate into Ly6C lo PD-L2 hi pro-resolving macrophages, via intermediate Ly6C hi PD-L2 hi macrophages but not Ly6C lo non-classical monocytes, in an IL-4 receptor-dependent manner. Along the differentiation, classical monocyte-derived macrophages display anti-inflammatory signatures followed by metabolic rewiring concordant with their ability to phagocytose apoptotic neutrophils and allergens, therefore contributing to the resolution of inflammation. The failure in the generation of these pro-resolving macrophages drives the IL-1α-mediated cycle of inflammation with abscess-like accumulation of necrotic neutrophils. Thus, we clarify the stepwise differentiation trajectory from Ly6C hi classical monocytes toward Ly6C lo pro-resolving macrophages that restrain neutrophilic aggravation of skin allergic inflammation., (© 2024. The Author(s).)

Basophils are the rarest granulocytes representing less than 1% of peripheral blood leukocytes. Even though basophils have been discovered more than 140 years ago, their roles in immune reactions had long been an enigma, partly because of their rarity and the similarity to tissue-resident mast cells. However, recent development of the analytical tools for basophil research, such as basophil-depletion antibody and basophil-related engineered mice, has uncovered the unique roles of basophils in various immune reactions. Basophils are now appreciated as a critical immune cell in various type 2-immune responses including the induction of chronic allergic inflammation and protective immunity against parasites. In this review, we summarize the recent understandings in the roles of basophils in allergic inflammation with especial focus on skin inflammation. We then focus on our recent findings in the differentiation and maturation pathways of basophils.

Myeloid cells are known to suppress antitumour immunity 1 . However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab 2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Atopic dermatitis (AD) is a heterogenous inflammatory skin disorder. Our previous study revealed that basophil infiltration in skin is observed in approximately 60% of AD cases. However, the clinical and histological characteristics of AD associated with basophil infiltration remain unclear. We examined basophil infiltration by immunohistochemical staining of 38 specimens from 34 patients who underwent skin biopsies to diagnose AD from April 2016 to September 2021 at Tokyo Medical and Dental University Hospital. The patients/specimens were divided into two groups, 17 patients/21 specimens associated with little or no basophil infiltration (basophil-low group) and 17 patients/17 specimens associated with marked basophil infiltration (basophil-high group). The clinical characteristics of the patients (age, sex, complications, blood biomarkers, skin symptoms, and treatment) and histological features of the specimens were compared between the groups. Basophil-high patients were significantly younger than basophil-low patients. Blood basophil counts were higher in basophil-high patients than in basophil-low patients. CD4 + T-cell infiltration was more marked in basophil-high specimens than in basophil-low specimens. CD4 + T cells infiltrated into the dermis as well as into the epidermis only in the basophil-high specimens. Thus, basophil-high AD can be characterized by skin lesions associated with abundant helper T-cell infiltration in younger patients., (© 2023 Japanese Dermatological Association.)

Basophils are the rarest granulocytes and are recognized as critical cells for type 2 immune responses. However, their differentiation pathway remains to be fully elucidated. Here, we assess the ontogenetic trajectory of basophils by single-cell RNA sequence analysis. Combined with flow cytometric and functional analyses, we identify c-Kit - CLEC12A hi pre-basophils located downstream of pre-basophil and mast cell progenitors (pre-BMPs) and upstream of CLEC12A lo mature basophils. The transcriptomic analysis predicts that the pre-basophil population includes previously-defined basophil progenitor (BaP)-like cells in terms of gene expression profile. Pre-basophils are highly proliferative and respond better to non-IgE stimuli but less to antigen plus IgE stimulation than do mature basophils. Although pre-basophils usually remain in the bone marrow, they emerge in helminth-infected tissues, probably through IL-3-mediated inhibition of their retention in the bone marrow. Thus, the present study identifies pre-basophils that bridge the gap between pre-BMPs and mature basophils during basophil ontogeny., (© 2023. The Author(s).)

Background: IL-31 is a type 2 cytokine involved in the itch sensation in atopic dermatitis (AD). The cellular origins of IL-31 are generally considered to be T H 2 cells. Macrophages have also been implicated as cellular sources of IL-31., Objective: We sought to determine the expression of IL-31 by macrophages and to elucidate the productive mechanisms and contributions to itch in AD skin lesions., Methods: Expression of IL-31 by macrophages, expressions of thymic stromal lymphopoietin (TSLP) and periostin, and presence of infiltrating basophils in human AD lesions were examined through immunofluorescent staining, and correlations were assessed. Furthermore, mechanisms of inducing IL-31-expressing macrophages were analyzed in an MC903-induced murine model for AD in vivo and in mouse peritoneal macrophages ex vivo., Results: A significant population of IL-31 + cells in human AD lesions was that of CD68 + cells expressing CD163, an M2 macrophage marker. The number of IL-31 + /CD68 + cells correlated with epidermal TSLP, dermal periostin, and the number of dermal-infiltrating basophils. In the MC903-induced murine AD model, significant scratching behaviors with enhanced expressions of TSLP and periostin were observed, accompanied by massive infiltration of basophils and IL-31 + /MOMA-2 + /Arg-1 + cells. Blockade of IL-31 signaling with anti-IL-31RA antibody or direct depletion of macrophages by clodronate resulted in attenuation of scratching behaviors. To effectively reduce lesional IL-31 + macrophages and itch, basophil depletion was essential in combination with TSLP- and periostin-signal blocking. Murine peritoneal macrophages produced IL-31 when stimulated with TSLP, periostin, and basophils., Conclusions: A network comprising IL-31-expressing macrophages, TSLP, periostin, and basophils plays a significant role in AD itch., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Aim: The functions of basophils have not been elucidated until recently because of their rarity. However, with recent developments in basophil-specific antibodies and basophil-deficient animals, the roles of basophils in various diseases related to chronic inflammation have been clarified. In this study, we aimed to investigate the roles of basophils in human ulcerative colitis (UC) and oxazolone (OXA) colitis using genetically engineered Mcpt8 DTR mice., Methods: Immunohistochemical staining of human colon specimens was performed to examine the involvement of basophils in the pathogenesis of UC. We examined the correlation between the number of infiltrating basophils and the UC endoscopic index of severity (UCEIS), Mayo score, and Matts score. We also examined the correlation between eosinophil count and basophil infiltration. In murine experiments, we examined whether basophil infiltration was involved in OXA-induced colitis and whether basophil depletion improved inflammation in Mcpt8 DTR mice., Results: Colonic basophil infiltration was significantly increased in patients with UC. There were significant correlations between UCEIS, Mayo score, Matts score, and the number of infiltrating basophils. In murine OXA-induced colitis, a significant increase in basophil infiltration was observed. When basophils were depleted by diphtheria toxin in Mcpt8 DTR mice, inflammation improved significantly and mRNA expression of some proinflammatory cytokines, including Tnf-α and Ifn-γ decreased significantly., Conclusion: Basophil infiltration correlated with endoscopic, clinical, and pathological scores in human UC independently of eosinophil infiltration, and depletion of basophils ameliorated mucosal inflammation in murine OXA-induced colitis, collectively suggesting that basophils exert a proinflammatory role in chronic intestinal inflammation such as UC., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Tissue-specific mouse models are essential tools to decipher the role of each cell compartment and/or their expressed genes in the pathophysiology of diseases. Here, we describe a new knock-in mouse model allowing expression of both the fluorescent protein tdTomato and the CRE recombinase selectively in the basophil compartment under the control of the Mcpt8 gene. These "CT-M8" mice did not show any abnormalities in their peripheral distribution of major immune cell populations nor their basophil function. CT-M8 mice allowed the identification of basophils by immunofluorescence and flow cytometry and basophil-specific Cre-mediated floxed gene deletion. Breeding of our CT-M8 mice with the ROSA26 flox-stop-DTA mice led to the generation of basophil-deficient mice with no detectable abnormalities in other cell compartments. These mice were then used to document basophil involvement in systemic lupus erythematosus (SLE) pathophysiology since we previously reported by transient depletion of these cells during the course of an ongoing disease that they support and amplify autoantibody production in two distinct lupus-like mouse models ( Lyn -/- and pristane-induced). Here, constitutive basophil deficiency prevented pristane-induced lupus-like disease development by limiting autoantibody titers and renal damages. Therefore, basophils have a nonredundant role in pristane-induced lupus-like disease and are involved in both its induction and amplification. This CT-M8 new mouse model will allow us to finely decipher the role of basophils and their expressed genes in health and disease., Competing Interests: CP and NC are coinventors of the patent WO2016128565A1 related to the use of PTGDR-1 and PTGDR-2 antagonists for the prevention or treatment of systemic lupus erythematosus. NC holds a patent related to compositions and methods for treating or preventing lupus (W020120710042). The remaining 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., (Copyright © 2022 Tchen, Simon, Chapart, Pellefigues, Karasuyama, Miyake, Blank, Benhamou, Daugas and Charles.)

Basophils are the rarest granulocytes and have long been overlooked in immunological research due to their rarity and similarities with tissue-resident mast cells. In the last two decades, non-redundant functions of basophils have been clarified or implicated in a broad spectrum of immune responses, particularly by virtue of the development of novel analytical tools for basophils. Basophils infiltrate inflamed tissues of patients with various disorders, even though they circulate in the bloodstream under homeostatic conditions. Depletion of basophils results in the amelioration or exaggeration of inflammation, depending on models of disease, indicating basophils can play either beneficial or deleterious roles in a context-dependent manner. In this review, we summarize the recent findings of basophil pathophysiology under various conditions in mice and humans, including allergy, autoimmunity, tumors, tissue repair, fibrosis, and COVID-19. Further mechanistic studies on basophil biology could lead to the identification of novel biomarkers or therapeutic targets in a broad range of diseases., 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., (Copyright © 2022 Miyake, Ito and Karasuyama.)

Objective: Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism., Design: We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging., Results: We obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgA tm/tm ) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA -/- ). IgA -/- exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4 + T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca 2+ biosensor showed that IgA -/- had elevated Ca 2+ signalling in Peyer's patch B cells. On the other hand, IgA tm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder., Conclusion: IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking. Here, we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Basophils, the rarest granulocytes, were identified by Paul Ehrlich more than 140 years ago, much earlier than the discovery of T and B cells. Unfortunately, basophils were often mixed up with tissue-resident mast cells because of some phenotypic similarities between them and considered erroneously as minor relatives or blood-circulating precursors of mast cells. Moreover, basophil research was hindered by the rarity of basophils and the paucity of useful analytical tools, and therefore basophils had often been neglected in immunological studies. A series of studies using newly developed tools, including basophil-depleting antibodies and genetically engineered mice deficient only in basophils, have clearly defined previously unrecognized roles of basophils, that are distinct from those played by tissue-resident mast cells. In this mini-review, we highlight recent advances in our understanding of basophil functions, particularly focusing on their roles in the regulation of innate and acquired immunity, allergic reactions, autoimmunity and protective immunity against parasitic infections, mainly based on animal studies. Further studies on human basophils would facilitate the development of new strategies for the treatment of basophil-associated disorders., (© The Japanese Society for Immunology. 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Superficial cutaneous Staphylococcus aureus (S. aureus) infection in humans can lead to soft tissue infection, an important cause of morbidity and mortality. IL-17A production by skin TCRγδ+ cells in response to IL-1 and IL-23 produced by epithelial and immune cells is important for restraining S. aureus skin infection. How S. aureus evades this cutaneous innate immune response to establish infection is not clear. Here we show that mechanical injury of mouse skin by tape stripping predisposed mice to superficial skin infection with S. aureus. Topical application of S. aureus to tape-stripped skin caused cutaneous influx of basophils and increased Il4 expression. This basophil-derived IL-4 inhibited cutaneous IL-17A production by TCRγδ+ cells and promoted S. aureus infection of tape-stripped skin. We demonstrate that IL-4 acted on multiple checkpoints that suppress the cutaneous IL-17A response. It reduced Il1 and Il23 expression by keratinocytes, inhibited IL-1+IL-23-driven IL-17A production by TCRγδ+ cells, and impaired IL-17A-driven induction of neutrophil-attracting chemokines by keratinocytes. IL-4 receptor blockade is shown to promote Il17a expression and enhance bacterial clearance in tape-stripped mouse skin exposed to S. aureus, suggesting that it could serve as a therapeutic approach to prevent skin and soft tissue infection.