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A common hallmark of several neuropsychiatric conditions is an altered protein homeostasis. In this context, ubiquitination has emerged as one of the most important post-translational modifications, regulating various intracellular processes such as protein degradation, autophagy, protein activation, and protein-protein interactions. Ubiquitination can be reversed by the activity of several deubiquitinating enzymes (DUBs), and it is of utmost importance that both processes remain in balance. Understanding the extent to which this system is involved in specific brain disorders opens up new possibilities for treating a broader spectrum of patients by targeting this central hub. In recent years, the attention to one of those DUBs, called CYLD, has increased sharply, but with relatively little focus on the central nervous system (CNS): 55 results for "CYLD Brain" vs. 895 results for "CYLD" in total (NCBI Pubmed search, 17.01.2025). Thus, we aim to provide a first overview of the new findings from the past decade specifically related to the role of CYLD in the physiology and pathology of the CNS., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: An increasing number of HCC develops in the context of metabolic dysfunction-associated steatotic liver disease and its inflammatory form, metabolic dysfunction-associated steatohepatitis, even in the absence of cirrhosis. Chronic metabolic inflammation is the driving force of metabolic dysfunction-associated steatotic liver disease progression and a key factor in hepatocarcinogenesis. Given the prominent role of IL-1 signaling in inflammation and metabolic diseases, we investigated the relevance of the hepatocyte-specific IL-1 receptor type 1 knockout in metabolic dysfunction-associated steatohepatitis-related noncirrhotic HCC., Methods: For HCC induction, Il1r1Hep-/- mice received a single i.p. injection of diethylnitrosamine at 2 weeks and were fed with high-fat plus high-carbohydrate diet, starting from 4 weeks. After 18 weeks of diet intervention, mice were sacrificed, and macroscopic and microscopic tumor loads were assessed., Results: Knockout of the hepatic IL-1 receptor type 1 pathway significantly reduced liver tumor growth. Il1r1Hep-/- mice were also less susceptible to hepatic steatosis, insulin resistance, and associated hepatic c-Jun N-terminal kinase activation than their wild-type (WT) littermates. Reduced Ki-67 and cyclin D1 levels, as well as decreased phosphorylation of signal transducer and activator of transcription 3, occur in Il1r1Hep-/- livers, lowering cancer cell proliferation and growth. Additionally, in Il1r1Hep-/- livers, the chemokine (C-X-C motif) ligand 1/2-driven accumulation of myeloid-derived suppressor cells and CD8+ T-cell infiltration were reduced compared to the wild type., Conclusions: Metabolic inflammation mediated by the hepatocytic IL-1 receptor type 1 is a cofactor in mutagenic hepatocarcinogenesis. Targeting IL-1 signaling could be an adjunct strategy to the current immunomodulatory HCC treatments., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The deubiquitinating enzyme CYLD negatively regulates NF-κB signaling by removing activating ubiquitin chains from several members of the NF-κB pathway. Thereby, CYLD is critical for the maintenance and differentiation of various immune cells. Despite the importance of the NF-κB pathway in microglia regulation, the role of CYLD in microglia has not been investigated so far. In this study, we investigated whether CYLD in microglia can protect against neuroinflammation using a newly generated conditional mouse strain (Rosa26-Cyld-tdTomato) that allows cell type-specific CYLD overexpression. Here, we show that overexpression of CYLD in microglia did not alter microglia numbers or microglia morphology in different brain regions. Additionally, CYLD overexpression did not modify the microglial response to LPS-induced neuroinflammation or the disease severity in experimental autoimmune encephalomyelitis (EAE). Finally, also immune cell infiltration into the CNS during EAE and under steady state conditions remained unaffected by microglial CYLD overexpression. Our findings suggest that CYLD overexpression does not alter microglial function, and thus does not represent a viable therapeutic strategy in neuroinflammatory conditions. This study highlights the complexity of ubiquitin-mediated signaling in neuroinflammation and the need for cell-type-specific investigations. The Rosa26-Cyld-tdTomato mouse model offers a valuable tool for studying CYLD's role across various tissues and cell types. KEY MESSAGES: Novel mouse strain for cell type-specific overexpression of the deubiquitinating enzyme CYLD. CYLD overexpression in microglia did not alter microglia numbers or morphology in the steady state. CYLD overexpression in microglia did not protect mice from LPS-induced neuroinflammation or EAE. CYLD overexpression in microglia did not influence their gene expression during neuroinflammation., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis., (© 2024. The Author(s).)

Prenatal imprinting to interleukin 17A (IL-17A) triggers behavioral disorders in offspring. However, reported models of maternal immune activation utilizing immunostimulants, lack specificity to elucidate the anatomical compartments of IL-17A's action and the distinct behavioral disturbances it causes. By combining transgenic IL-17A overexpression with maternal deficiency in its receptor, we established a novel model of prenatal imprinting to maternal IL-17A (acronym: PRIMA-17 model). This model allowed us to study prenatal imprinting established exclusively through embryo-restricted IL-17A responses. We demonstrated a transfer of transgenic IL-17A across the placental barrier, which triggered the development of selected behavioral deficits in mouse offspring. More specifically, embryonic responses to IL-17A resulted in communicative impairment in early-life measured by reduced numbers of nest retrieval calls. In adulthood, IL-17A-imprinted offspring displayed an increase in anxiety-like behavior. We advocate our PRIMA-17 model as a useful tool to study neurological deficits in mice., (© 2024. The Author(s).)

The intestinal lamina propria (LP) is a leukocyte-rich cornerstone of the immune system owing to its vital role in immune surveillance and barrier defense against external pathogens. Here, we present a protocol for isolating and analyzing immune cell subsets from the mouse intestinal LP for further downstream applications. Starting from tissue collection and cleaning, epithelium removal, and enzymatic digestion to collection of single cells, we explain each step in detail to maximize the yield of immune cells from the intestinal LP., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B ( CD81 , BACH2 , and NEAT1 ) or T ( GATA3 , TOX , and PDCD1 ) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional TNFAIP3 knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB-mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized.

In this issue of Neuron, Chadarevian et al. 1 and Munro et al. 2 demonstrate how the absence of homeostatic microglia leads to severe neuropathologies, including axonal spheroids, calcifications, myelination abnormalities, and gliosis, associated with leukoencephalopathy and age-related neurodegeneration. Transplantation of healthy microglia can reverse these conditions, opening new avenues for therapeutic research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

B-1 cells have intricate biology, with distinct function, phenotype and developmental origin from conventional B cells. They generate a B cell receptor with conserved germline characteristics and biased V(D)J recombination, allowing this innate-like lymphocyte to spontaneously produce self-reactive natural antibodies (NAbs) and become activated by immune stimuli in a T cell-independent manner. NAbs were suggested as "rheostats" for the chronic diseases in advanced age. In fact, age-dependent loss of function of NAbs has been associated with clinically-relevant diseases in the elderly, such as atherosclerosis and neurodegenerative disorders. Here, we analyzed comprehensively the ontogeny, phenotypic characteristics, functional properties and emerging roles of B-1 cells and NAbs in health and disease. Additionally, after navigating through the complexities of B-1 cell biology from development to aging, therapeutic opportunities in the field are discussed., (© 2024. The Author(s).)

Aims: The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease., Methods and Results: Interleukin-6-overexpressing (IL-6 OE ) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6 OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6 OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6 OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner., Conclusion: Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease., Competing Interests: Conflict of interest: M.B. received funding and is a consultant for ARCA Biopharma (not related to the presented work). S.K. received funding for consultant lectures from Almiral and Jansson-Cilag (not related to the presented work either)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective parameters to quantify psoriatic inflammation are needed for interdisciplinary patient care, as well as preclinical experimental models. This study evaluates neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in psoriasis patients and five murine models of psoriasis-like skin disease based on topical imiquimod application and overexpression of IL-17A under different promotors. We performed a single-center prospective observational study in a German population, investigating psoriasis patients prior to, 4 weeks, and 16 weeks post begin of systemic anti-inflammatory therapy. Psoriasis area and severity index (PASI), blood count, and C-reactive protein (CRP) levels were attained at each timepoint. Additionally, five murine models of psoriasis-like skin disease involving five distinct experimental procedures differing in time of disease-onset and severity were investigated regarding PLR and NLR. Of 43 recruited psoriasis patients, 34 patients were followed up to 16 weeks. The cohort was 69.77% male, showing a median age of 32.0 years (range 19.0-67.0; IQR 26). The median PASI decreased from 16.35 (8.0-50.0; 10.20) to 1.6 (0-10.3; 2.56) after 16 weeks of systemic therapy. Spearman's correlation showed statistically significant positive correlation for NLR with PASI (r s  = 0.27, p = 0.006), however not for PLR. NLR, but not PLR, was significantly associated with PASI in a multiple linear regression analysis including age, sex, psoriasis arthritis, and smoking. In the murine models of psoriasis-like skin disease, both NLR and PLR were significantly increased in the acute-severe models compared to controls (p < 0.001, p = 0.005, and p = 0.02, respectively), demonstrating gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR was significantly associated with PASI in psoriatic patients as well as psoriatic phenotype in different murine psoriasis models. Our data warrants investigation of NLR in psoriasis patients and preclinical psoriasis models as an objective biomarker of psoriatic skin inflammation. KEY MESSAGES : NLR, but not PLR, showed a statistically significant positive correlation with Psoriasis Area and Severity Index (PASI) in our human psoriasis cohort. Both NLR and PLR were significantly increased in murine psoriasis models compared to matched controls, with gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR may represent an easily available, cheap, and objective parameter to monitor psoriatic inflammation in both clinical patient routine, as well as preclinical experimental murine models., (© 2023. The Author(s).)

Background & Aims: Hepatocellular necrosis is common in both acute and chronic liver injury and may evolve to fibrosis and liver failure. Injury leads to accumulation of necrotic cell debris in the liver, which drives persistent inflammation and poor recovery. This study investigated the role of natural antibodies (NAbs) in the clearance of necrotic cells in the injured liver, their impact on tissue regeneration and their potential as a therapy for acute liver injury., Methods: We used murine models of drug-induced liver injury and focal thermal injury in immunocompetent and antibody-deficient mice ( Rag2 -/- and IgMi). Intravital microscopy was used to investigate the role of NAbs in the phagocytosis of necrotic cells in the liver in vivo . Immunostainings were used to quantify the extent of liver necrosis (fibrin), antibody deposition (IgM and IgG) and cellular proliferation (Ki67)., Results: Both IgM and IgG NAbs bound necrotic liver areas and opsonized multiple debris molecules released during hepatocellular necrosis such as DNA, histones, actin, phosphoinositides and mitochondrial cardiolipin, but not phosphatidylserine. Rag2 -/- and IgMi mice presented impaired recovery from liver injury, which was correlated to the sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. These defects were rescued by treating mice with NAbs after the induction of injury. Mechanistically, in vitro and in vivo , phagocytosis of necrotic debris was dependent on NAbs via Fcγ receptors and CD11b. Moreover, NAb-mediated phagocytosis of necrotic cell debris occurs in two waves, firstly driven by neutrophils and then by recruited monocytes. Importantly, supplementation of immunocompetent mice with NAbs also improved liver regeneration significantly, demonstrating the therapeutic potential of natural IgM and IgG., Conclusion: NAbs drive the phagocytosis of necrotic cells in liver injury and promote liver regeneration and recovery., Impact and Implications: Treatment with natural antibodies after acute liver injury improved recovery by increasing the clearance of necrotic debris and by improving cellular proliferation in the liver. This preclinical study provides a basis for the development of an immunotherapy for patients with early-stage, reversible, liver injury that aims to prevent disease chronification into fibrosis and liver failure., Competing Interests: The authors have no conflicts to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs). Accordingly, depleting BAMs, deleting IL-17 receptor A in brain macrophages or suppressing meningeal T cells rescues cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. Our data unveil a critical role of meningeal T cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction in a mouse model of HTN., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20ΔCNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL to be expressed by A20-deficient CNS-ECs, which we found to function as adhesion molecules. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20ΔCNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in WT mice. In addition, blocking of ICOSL on primary mouse brain microvascular ECs impaired the adhesion of T cells in vitro. Taken together, we propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.

Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease's development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses pro-inflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities., Competing Interests: SMK is employed by Boehringer Ingelheim Pharma GmbH & Co. KG. SK declares having received consultancy honorary from Almirall and lecture honoraria from Janssen-Cilag, which both was not associated with this work. 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 © 2023 Fischer, Kübelbeck, Kolb, Ringen, Waisman, Wittmann, Karbach, Kölsch and Kramer.)

Objective: Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS)., Design: EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared., Results: Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls., Conclusions: Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease., 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.)

AIM2 is an interferon-inducible HIN-200 protein family member and is well-documented for its roles in innate immune responses as a DNA sensor. Recent studies have highlighted AIM2's function on regulatory T cells (Treg) and follicular T cells (Tfh). However, its involvement in Th17 cell differentiation remains unclear. This study reveals that AIM2 promotes Th17 cell differentiation. AIM2 deficiency decreases IL-17A production and downregulates key Th17 associated proteins (RORγt, IL-1R1, IL-23R). AIM2 is located in the nucleus of Th17 cells, where it interacts with RORγt, enhancing its binding to the Il17a promoter. The absence of AIM2 hinders naive CD4 T cells from differentiating into functional Th17 cells and from inducing colitis in Rag1 -/- mice. This study uncovers AIM2's role as a regulator of Th17 cell transcriptional programming, highlighting its potential as a therapeutic target for Th17 cell-mediated inflammatory diseases., Competing Interests: The authors declare no competing financial interests., (© 2023 The Author(s).)

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFβ and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly ( P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls ( n = 10). The pulmonary sources of externalized histones were Ly6G + CD11b + neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFβ1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM + cells to antagonize macrophage-derived IL-27 production. TGFβ1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFβ1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.

Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin-specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke-induced neuronal loss and neurological deficits by inhibiting microglia-mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF-κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63-specific polyubiquitin chains from TAB2. AAV9-mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A + γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.

Psoriasis is a chronic inflammatory skin disorder driven by the IL-23/type 3 immune response. However, molecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, which was confirmed in lesioned skin from patients with psoriasis and preclinical psoriasiform skin inflammation models. Genetic ablation or pharmacologic inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type 3 immunity in psoriasiform skin inflammation. In addition, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we showed an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type 3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8 + T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC., Design: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra -/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1 nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models., Results: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1 -/- and Foxn1 nu/nu mice, respectively. Finally, Il17ra -expressed by fibroblasts was required for Tc17-driven tumour growth in vivo., Conclusions: We identified Tc17 as a novel protumourigenic CD8 + T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Interleukin (IL)-17 protects epithelial barriers by inducing the secretion of antimicrobial peptides. However, the effect of IL-17 on Paneth cells (PCs), the major producers of antimicrobial peptides in the small intestine, is unclear. Here, we show that the targeted ablation of the IL-17 receptor (IL-17R) in PCs disrupts their antimicrobial functions and decreases the frequency of ileal PCs. These changes become more pronounced after colonization with IL-17 inducing segmented filamentous bacteria. Mice with PCs that lack IL-17R show an increased inflammatory transcriptional profile in the ileum along with the severity of experimentally induced ileitis. These changes are associated with a decrease in the diversity of gut microbiota that induces a severe ileum pathology upon transfer to genetically susceptible mice, which can be prevented by the systemic administration of IL-17a/f in microbiota recipients. In an exploratory analysis of a small cohort of pediatric patients with Crohn's disease, we have found that a portion of these patients exhibits a low number of lysozyme-expressing ileal PCs and a high ileitis severity score, resembling the phenotype of mice with IL-17R-deficient PCs. Our study identifies IL-17R-dependent signaling in PCs as an important mechanism that maintains ileal homeostasis through the prevention of dysbiosis., 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 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC., Methods: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans., Results: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis., Conclusions: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH., Impact and Implications: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc ), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc -deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection., Competing Interests: Declaration of Interests The authors declare no competing interests.

Keratinocytes (KCs) form the outer epithelial barrier of the body, protecting against invading pathogens. Mice lacking the IL-17RA or both IL-17A and IL-17F develop spontaneous Staphylococcusaureus skin infections. We found a marked expansion of T 17 cells, comprised of RORγt-expressing γδ T cells and T helper 17 cells in the skin-draining lymph nodes of these mice. Contradictory to previous suggestions, this expansion was not a result of a direct negative feedback loop because we found no expansion of T 17 cells in mice lacking IL-17 signaling specifically in T cells. Instead, we found that the T 17 expansion depended on the microbiota and was observed only when KCs were deficient for IL-17RA signaling. Indeed, mice that lack IL-17RA only in KCs showed an increased susceptibility to experimental epicutaneous infection with S. aureus together with an accumulation of IL-17A-producing γδ T cells. We conclude that deficiency of IL-17RA on KCs leads to microbiota dysbiosis in the skin, which triggers the expansion of IL-17A-producing T cells. Our data show that KCs are the primary target cells of IL-17A and IL-17F, coordinating the defense against microbial invaders in the skin., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis is an immune-mediated inflammatory skin disease driven by interleukin-17A (IL-17A) and associated with cardiovascular dysfunction. We used a severe psoriasis mouse model of keratinocyte IL-17A overexpression (K14-IL-17A ind/+ , IL-17A ind/+ control mice) to investigate the activity of neutrophils and a potential cellular interconnection between skin and vasculature. Levels of dermal reactive oxygen species (ROS) and their release by neutrophils were measured by lucigenin-/luminol-based assays, respectively. Quantitative RT-PCR determined neutrophilic activity and inflammation-related markers in skin and aorta. To track skin-derived immune cells, we used PhAM-K14-IL-17A ind/+ mice allowing us to mark all cells in the skin by photoconversion of a fluorescent protein to analyze their migration into spleen, aorta, and lymph nodes by flow cytometry. Compared to controls, K14-IL-17A ind/+ mice exhibited elevated ROS levels in the skin and a higher neutrophilic oxidative burst accompanied by the upregulation of several activation markers. In line with these results psoriatic mice displayed elevated expression of genes involved in neutrophil migration (e.g., Cxcl2 and S100a9) in skin and aorta. However, no direct immune cell migration from the psoriatic skin into the aortic vessel wall was observed. Neutrophils of psoriatic mice showed an activated phenotype, but no direct cellular migration from the skin to the vasculature was observed. This suggests that highly active vasculature-invading neutrophils must originate directly from the bone marrow. Hence, the skin-vasculature crosstalk in psoriasis is most likely based on the systemic effects of the autoimmune skin disease, emphasizing the importance of a systemic therapeutic approach for psoriasis patients., (© 2023 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Background: There is a growing understanding of inflammation in psoriasis beyond its dermatological manifestation, towards systemic inflammation. Management of possible comorbidities encompassing psychological, metabolic and cardiovascular disease is recommended in national and international dermatology guidelines for treatment of psoriasis patients. Vice versa, psoriasis is being recognized as a new risk factor for cardiovascular inflammation within the cardiological community., Methods: A review of the literature was conducted. Key points regarding epidemiological, mechanistic and management aspects were summarized and put into context for physicians treating psoriasis patients., Results: Efforts are currently being made to better understand the mechanistic underpinnings of systemic inflammation within psoriatic inflammation. Studies looking to "hit two birds with one stone" regarding specifically cardiovascular comorbidities of psoriasis patients using established systemic dermatological therapies have so far provided heterogeneous data. The diagnosis of psoriasis entails preventive and therapeutic consequences regarding concomitant diseases for the individual patient., Conclusions: The knowledge of comorbidities in psoriasis calls for pronounced interdisciplinary care of psoriasis patients, to which this article highlights efforts regarding vascular inflammation and cardiovascular disease., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In the central nervous system (CNS), insulin-like growth factor 1 (IGF-1) regulates myelination by oligodendrocyte (ODC) precursor cells and shows anti-apoptotic properties in neuronal cells in different in vitro and in vivo systems. Previous work also suggests that IGF-1 protects ODCs from cell death and enhances remyelination in models of toxin-induced and autoimmune demyelination. However, since evidence remains controversial, the therapeutic potential of IGF-1 in demyelinating CNS conditions is unclear. To finally shed light on the function of IGF1-signaling for ODCs, we deleted insulin-like growth factor 1 receptor (IGF1R) specifically in mature ODCs of the mouse. We found that ODC survival and myelin status were unaffected by the absence of IGF1R until 15 months of age, indicating that IGF-1 signaling does not play a major role in post-mitotic ODCs during homeostasis. Notably, the absence of IGF1R did neither affect ODC survival nor myelin status upon cuprizone intoxication or induction of experimental autoimmune encephalomyelitis (EAE), models for toxic and autoimmune demyelination, respectively. Surprisingly, however, the absence of IGF1R from ODCs protected against clinical neuroinflammation in the EAE model. Together, our data indicate that IGF-1 signaling is not required for the function and survival of mature ODCs in steady-state and disease., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Psoriasis is an inflammatory skin disease characterized by keratinocyte proliferation and inflammatory cell infiltration induced by IL-17. However, the molecular mechanism through which IL-17 signaling in keratinocytes triggers skin inflammation remains not fully understood. Pyruvate kinase M2 (PKM2), a glycolytic enzyme, has been shown to have non-metabolic functions. Here, we report that PKM2 mediates IL-17A signaling in keratinocytes triggering skin psoriatic inflammation. We find high expression of PKM2 in the epidermis of psoriatic patients and mice undergoing psoriasis models. Specific depletion of PKM2 in keratinocytes attenuates the development of experimental psoriasis by reducing the production of pro-inflammatory mediators. Mechanistically, PKM2 forms a complex with Act1 and TRAF6 regulating NF-κB transcriptional signaling downstream of the IL-17 receptor. As IL-17 also induces PKM2 expression in keratinocytes, our findings reveal a sustained signaling circuit critical for the psoriasis-driving effects of IL-17A, suggesting that PKM2 is a potential therapeutic target for psoriasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β2-integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell-DC interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.

Objective: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory signaling, whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways., Methods: Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition, and DEN-induced HCC. To this end, we performed dietary and chemical interventions in mice that were analyzed via single nucleus sequencing, gene expression and histochemical methods. Ultimately, we verified our mouse results in human patient samples., Results: We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NFκB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans., Conclusions: Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Aims: Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and γδ T cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδ T cells in atherosclerosis., Methods and Results: IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδ T cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδ T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδ T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators., Conclusions: IL-23R+ γδ T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The oligodendrocyte (OL) lineage transcription factor Olig2 is expressed throughout oligodendroglial development and is essential for oligodendroglial progenitor specification and differentiation. It was previously reported that deletion of Olig2 enhanced the maturation and myelination of immature OLs and accelerated the remyelination process. However, by analyzing multiple Olig2 conditional KO mouse lines (male and female), we conclude that Olig2 has the opposite effect and is required for OL maturation and remyelination. We found that deletion of Olig2 in immature OLs driven by an immature OL-expressing Plp1 promoter resulted in defects in OL maturation and myelination, and did not enhance remyelination after demyelination. Similarly, Olig2 deletion during premyelinating stages in immature OLs using Mobp or Mog promoter-driven Cre lines also did not enhance OL maturation in the CNS. Further, we found that Olig2 was not required for myelin maintenance in mature OLs but was critical for remyelination after lysolecithin-induced demyelinating injury. Analysis of genomic occupancy in immature and mature OLs revealed that Olig2 targets the enhancers of key myelination-related genes for OL maturation from immature OLs. Together, by leveraging multiple immature OL-expressing Cre lines, these studies indicate that Olig2 is essential for differentiation and myelination of immature OLs and myelin repair. Our findings raise fundamental questions about the previously proposed role of Olig2 in opposing OL myelination and highlight the importance of using Cre-dependent reporter(s) for lineage tracing in studying cell state progression. SIGNIFICANCE STATEMENT Identification of the regulators that promote oligodendrocyte (OL) myelination and remyelination is important for promoting myelin repair in devastating demyelinating diseases. Olig2 is expressed throughout OL lineage development. Ablation of Olig2 was reported to induce maturation, myelination, and remyelination from immature OLs. However, lineage-mapping analysis of Olig2 -ablated cells was not conducted. Here, by leveraging multiple immature OL-expressing Cre lines, we observed no evidence that Olig2 ablation promotes maturation or remyelination of immature OLs. Instead, we find that Olig2 is required for immature OL maturation, myelination, and myelin repair. These data raise fundamental questions about the proposed inhibitory role of Olig2 against OL maturation and remyelination. Our findings highlight the importance of validating genetic manipulation with cell lineage tracing in studying myelination., (Copyright © 2022 the authors.)

Chronic stress is a major risk factor for developing psychiatric conditions. In addition to elevating the levels of stress hormones released in the body, chronic stress activates the immune system, resulting in increased levels of proinflammatory cytokines and innate immune cells in the circulation of rodents and humans. Furthermore, exposure to chronic stress alters the phenotype of microglia, a population of innate immune cells that reside in the CNS parenchyma. In rodent models, chronic stress activates microglia in defined brain regions and induces changes in their phenotype and functional properties. In this review, we discussed how microglia are activated in stressful situations. Furthermore, we described how microglia affect the CNS environment during chronic stress, through the production of cytokines, the induction of reactive oxygen species, and phagocytosis. We suggested that, due to their strategic location as immune cells within the CNS, microglia are important players in the induction of psychopathologies after chronic stress., (© 2022 American Academy of Neurology.)

Interactions between the mammalian host and commensal microbiota are enforced through a range of immune responses that confer metabolic benefits and promote tissue health and homeostasis. Immunoglobulin A (IgA) responses directly determine the composition of commensal species that colonize the intestinal tract but require substantial metabolic resources to fuel antibody production by tissue-resident plasma cells. Here, we demonstrate that IgA responses are subject to diurnal regulation over the course of a circadian day. Specifically, the magnitude of IgA secretion, as well as the transcriptome of intestinal IgA + plasma cells, was found to exhibit rhythmicity. Oscillatory IgA responses were found to be entrained by time of feeding and were also found to be in part coordinated by the plasma cell-intrinsic circadian clock via deletion of the master clock gene Arntl . Moreover, reciprocal interactions between the host and microbiota dictated oscillatory dynamics among the commensal microbial community and its associated transcriptional and metabolic activity in an IgA-dependent manner. Together, our findings suggest that circadian networks comprising intestinal IgA, diet, and the microbiota converge to align circadian biology in the intestinal tract and to ensure host-microbial mutualism.

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic as well as systemic insulin resistance even in the absence of type 2 diabetes. The extent and pathways through which hepatic inflammation modulates insulin sensitivity in NAFLD are only partially understood. We explored the contribution of hepatic interleukin (IL)-1 signalling in a novel conditional knockout mouse model and expand the knowledge on this signalling pathway with regard to its liver-specific functions., Methods: A high-fat, high-carbohydrate diet (HFD) over 12 weeks was used in male hepatocyte-specific IL-1 receptor type 1 (IL-1R1) knockout mice (Il1r1 Hep-/- ) and wild-type (WT) littermates., Results: Both genotypes developed an obese phenotype and accompanying macrovesicular hepatic steatosis. In contrast to WT mice, microvesicular steatosis and ballooning injury was less pronounced in HFD-fed Il1r1 Hep-/- mice, and alanine aminotransferase remained in the normal range. This was paralleled by the suppression of injurious and proinflammatory hepatic c-Jun N-terminal kinases and extracellular signal-regulated kinases signalling, stable peroxisome proliferator activated receptor gamma coactivator-1alpha and farnesoid X receptor-alpha expression and preservation of mitochondrial function. Strikingly, despite HFD-feeding Il1r1 Hep-/- mice remained highly insulin sensitive as indicated by lower insulin levels, homeostatic model assessment for insulin resistance, higher glucose tolerance, more stable hepatic insulin signalling cascade, and less adipose tissue inflammation compared to the WT., Conclusions: The current data highlights that hepatocyte IL-1R1 contributes to hepatic and extrahepatic insulin resistance. Future liver-directed therapies in NAFLD could have effects on insulin sensitivity when improving hepatic inflammation and IL-1R1 signalling., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2-6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific β2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of β2 integrins in vivo.

Acute liver failure (ALF) is a rare entity but exhibits a high mortality. The mechanisms underlying ALF are not completely understood. The present study explored the role of the hepatic B cell leukemia-3 (Bcl-3), a transcriptional regulator of nuclear factor-kappa B (NF-κB), in two independent models of ALF. We employed a recently developed transgenic mouse model in a C57BL6/J background comparing wild-type (WT) and transgenic littermates with hepatocyte-specific overexpression of Bcl-3 (Bcl-3 Hep ) in the ALF model of d-galactosamine (d-GalN) and lipopolysaccharide (LPS). Additionally, the apoptosis-inducing CD95 (FAS/APO-1)-ligand was explored. Bcl-3 Hep mice exhibited a significant protection from ALF with decreased serum transaminases, decreased activation of the apoptotic caspases 8, 9, and 3, lower rates of oxidative stress, B-cell lymphoma 2 like 1 (BCL2L1/BCL-X L ) degradation and accompanying mitochondrial cytochrome c release, and ultimately a decreased mortality rate from d-GalN/LPS compared to WT mice. d-GalN/LPS treatment resulted in a marked inflammatory cytokine release and stimulated the activation of signal transducer and activator of transcription (STAT) 3, c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) signaling comparably in the hepatic compartment of Bcl-3 Hep and WT mice. However, in contrast to the WT, Bcl-3 Hep mice showed a diminished rate of IkappaB kinase-beta (IKK-β) degradation, persistent receptor interacting protein kinase (RIPK) 1 function and thus prolonged cytoprotective nuclear factor-kappa B (NF-κB) p65 signaling through increased p65 stability and enhanced transcription. Likewise, Bcl-3 overexpression in hepatocytes protected from ALF with massive hepatocyte apoptosis induced by the anti-FAS antibody Jo2. The protection was also linked to IKK-β stabilization. Overall, our study showed that Bcl-3 rendered hepatocytes more resistant to hepatotoxicity induced by d-GalN/LPS and FAS-ligand. Therefore, Bcl-3 appears to be a critical regulator of the dynamics in ALF through IKK-β., (© 2022. The Author(s).)

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract. Although the pathophysiology of IBD is multifaceted, ubiquitination, a post-translational modification, has been shown to have essential roles in its pathogenesis and development. Ubiquitin-modifying enzymes (UMEs) work in synergy to orchestrate the optimal ubiquitination of target proteins, thereby maintaining intestinal homeostasis. Genome-wide association studies (GWAS) have identified multiple UME genes as IBD susceptibility loci, implying the importance of UMEs in IBD. Furthermore, accumulative evidence demonstrates that UMEs affect intestinal inflammation by regulating various aspects, such as intestinal barrier functions and immune responses. Considering the significant functions of UMEs in IBD, targeting UMEs could become a favorable therapeutic approach for IBD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, significantly contributing to the maintenance and reestablishment of immune homeostasis. Accordingly, it has been shown in the intestine that IL-10 produced by Tregs can act on effector T cells, thereby limiting inflammation. Herein, we investigate whether this role also applies to IL-10 produced by T cells during central nervous system (CNS) inflammation. During neuroinflammation, both CNS-resident and -infiltrating cells produce IL-10; yet, as IL-10 has a pleotropic function, the exact contribution of the different cellular sources is not fully understood. We find that T-cell-derived IL-10, but not other relevant IL-10 sources, can promote inflammation in experimental autoimmune encephalomyelitis. Furthermore, in the CNS, T-cell-derived IL-10 acts on effector T cells, promoting their survival and thereby enhancing inflammation and CNS autoimmunity. Our data indicate a pro-inflammatory role of T-cell-derived IL-10 in the CNS., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease., Competing Interests: DH, JL, GM, AL, AW, KN, PW, DB No competing interests declared, WM Reviewing editor, eLife, (© 2022, Heo et al.)

In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that "natural" cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. KEY MESSAGES: We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM., (© 2021. The Author(s).)

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin-17A (IL-17A)-mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti-inflammatory treatment by tumor necrosis factor (TNF)-α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium-dependent vascular tone were assessed by ultrasound measurement of flow-mediated dilation (FMD) and low-flow-mediated constriction (l-FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti-TNF-α treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti-TNF-α treatment significantly improved l-FMC in psoriasis patients. Noteworthy, both FMD and l-FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co-existent classical cardiovascular risk factors on FMD and l-FMC cannot be ruled out by our small study. The results suggest that anti-inflammatory treatment with TNF-α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti-inflammatory therapy on vascular function in patients with chronic inflammatory diseases., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)