Abstract
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.
Highlights
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, characterized by skin lesions, pruritic excoriations and susceptibility to cutaneous infections [1]
Co-culture system produced significantly higher release of inflammatory cytokines and chemokines upon IL-31 and IL-33 stimulation compared with single culture, suggesting that the interplay between EOS and human dermal fibroblast (HDF) was essential for exacerbation of an inflammation cascade
In vivo differentiation and the balance of T cells, and recruitment experiments with the combination of metabolomics and of immune cells upon antigen presentation, as well as microbiota amplicon were conducted in this study to explore the anti-inflammatory mechanism of IL-37 for the potential treatment of AD, by focusing on the regulation of immunity through autophagy
Summary
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, characterized by skin lesions, pruritic excoriations and susceptibility to cutaneous infections [1]. There is no definitive cure for AD and the current treatment with immunosuppressive corticosteroid is associated with undesirable side effects. Eosinophils (EOS), as the principal effector cells of allergic inflammation including AD [2], their accumulation and infiltration in tissues are mediated by the specific eosinophil chemokine eotaxin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin [2, 3]. IL37 can be expressed by regulatory T cells (Treg) to enhance the expression of IL-10, Foxp, and cytotoxic T-lymphocyte associated antigen-4 to promote the immunosuppressive activity of human Treg cells [6]. Receptor IL-18Rα and IL-1R8 can mediate the multifaceted anti-inflammatory activity of IL-37, via the regulation of cellular adhesion and migration, and intracellular signal transduction mechanism [4, 7]. This study was performed to investigate the anti-inflammatory mechanisms of IL-37 in AD by using recombinant human IL-37b and CRISPR/Cas human IL-37b knock-in mice
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