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IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis.

ABSTRACT: Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.

SUBMITTER: Hou T

PROVIDER: S-EPMC8304334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IL-37 Ameliorating Allergic Inflammation in Atopic Dermatitis Through Regulating Microbiota and AMPK-mTOR Signaling Pathway-Modulated Autophagy Mechanism.

Project description:Interaction between eosinophils and dermal fibroblasts is essential for provoking allergic inflammation in atopic dermatitis (AD). In vitro co-culture of human eosinophils and dermal fibroblasts upon AD-related IL-31 and IL-33 stimulation, and in vivo MC903-induced AD murine model were employed to investigate the anti-inflammatory mechanism of IL-1 family cytokine IL-37 in AD. Results showed that IL-37b could inhibit the in vitro induction of AD-related pro-inflammatory cytokines IL-6 and TNF-α, and chemokines CXCL8, CCL2 and CCL5, increase autophagosome biogenesis-related LC3B, and decrease autophagy-associated ubiquitinated protein p62 by regulating intracellular AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway. In CRISPR/Cas9 human IL-37b knock-in mice, IL-37b could significantly alleviate MC903-stimulated ear tissue swelling, itching sensation and the level of circulating cytokine IL-6 and ear in situ expression of AD-related TNF-α, CCL5 and transforming growth factor-β. Moreover, IL-37b could significantly upregulate Foxp3+ regulatory T cells (Treg) in spleen and ear together with significantly increased serum Treg cytokine IL-10, and decrease eosinophil infiltration in ear lesion. IL-37b knock-in mice showed a distinct intestinal microbiota metabolic pattern upon MC903 stimulation. Furthermore, IL-37b restored the disordered gut microbiota diversity, through regulating the in vivo autophagy mechanism mediated by intestinal metabolite 3-methyladenine, adenosine monophosphate, 2-hydroxyglutarate, purine and melatonin. In summary, IL-37b could significantly ameliorate eosinophils-mediated allergic inflammation via the regulation of autophagy mechanism, intestinal bacterial diversity and their metabolites in AD. Results therefore suggest that IL-37 is a potential anti-inflammatory cytokine for AD treatment.

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Combination of FLG mutations and SNP of TSLP (rs1898671) influence on atopic dermatitis occurrence.

Project description:IntroductionAtopic dermatitis (AD) is a common, chronic, relapsing and heterogeneous inflammatory skin disease. Its main causes are genetic predispositions, the epidermal barrier defect, and immune system dysfunction. Thymic stromal lymphopoietin (TSLP) is highly expressed in the epidermis of AD patients and its production is triggered by exposure to environmental factors, allergens, microorganisms and irritants.AimTo search for the associations between rs1898671 polymorphism in the promotor region of the TSLP gene (SNP) and AD occurrence and course.Material and methodsThe frequency of polymorphism occurrence was examined, connection with IgE level, the severity of AD, itching, and concomitant asthma occurrence and combination with FLG gene mutations (2282del4, R501X) in the population of northern Poland. Blood samples were collected from 239 patients with AD and 170 controls. SNP of TSLP and FLG null mutations were analysed. PCR and RFLP restriction fragment length polymorphism analysis was used.ResultsNo polymorphisms of studied cytokines caused more frequent occurrence of AD compared to controls. We found no associations between TSLP gene polymorphism and AD severity (p = 0.395), IgE level (p = 0.895), VAS (p = 0.918) or concomitant asthma (p = 0.742).ConclusionsThe SNP of TSLP rs1898671 does not influence the AD course and occurrence. 2282del4 FLG mutation is a key influencer in AD. However, the coexistence of FLG mutations and SNP of TSLP may play a protective role.

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Bidirectional associations between eosinophils, basophils, and lymphocytes with atopic dermatitis: A multivariable Mendelian randomization study.

Project description:BackgroundDespite being prone to reverse causation and having unmeasured confounding factors, many clinical observational studies have highlighted the critical association between basophils, eosinophils, and lymphocytes and atopic dermatitis (AD). Whether these cells play a causal role in AD development remains uncertain.MethodsData were obtained from the UK Biobank and the Blood Cell Consortium, from a large publicly available genome-wide association study (GWAS) with more than 500,000 subjects of European ancestry and for AD from three independent cohorts with more than 700,000 subjects of European ancestry. We performed single-variable Mendelian randomization (SVMR), followed by multivariable Mendelian randomization (MVMR) to assess the total and direct effects of immune cell counts on AD risk.ResultsSVMR estimates showed that genetically predicted higher eosinophil [odds ratio (OR): 1.23, 95% confidence interval (CI): 1.17-1.29, p = 5.85E-16] and basophil counts (OR: 1.11, 95% CI: 1.03-1.19, p = 0.004) had an adverse effect on the risk of AD, while a higher lymphocyte count (OR: 0.93, 95% CI: 0.89-0.98, p = 0.006) decreased the risk. Reverse MR analysis showed higher basophil (beta: 0.04, 95% CI: 0.01-0.07, p = 0.014) and lower lymphocyte counts (beta: -0.05, 95% CI: -0.09 to -0.01, p = 0.021) in patients with AD. In MVMR, the effects of eosinophils (OR: 1.19, 95% CI: 1.09-1.29, p = 8.98E-05), basophils (OR: 1.19, 95% CI: 1.14-1.24, p = 3.72E-15), and lymphocytes (OR: 0.93, 95% CI: 0.89-0.98, p = 0.006) were still significant.DiscussionMendelian randomization (MR) findings suggest that an increase in the eosinophil and basophil counts and a decrease in the lymphocyte counts are potential causal risk factors for AD. These risk factors are independent of each other.

| S-EPMC9780468 | biostudies-literature

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