Effect of anti-inflammatory IL-37 on ameliorating atopic dermatitis via enhancing AMPK-mTOR -dependent autophagy
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Interaction between eosinophils and dermal fibroblasts is essential for allergic inflammation, which is the crucial part of immunopathological mechanism in atopic dermatitis (AD). Anti-inflammatory IL-1 family cytokine IL-37 has been reported to alleviate inflammation by regulating intracellular AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling, which is a key regulator of autophagy. Anti-inflammatory effect of IL-37 on allergic inflammation by regulating AMPK-mTOR-dependent autophagy is investigated using in vivo and in vitro AD model.
Human eosinophils (EOS) and dermal fibroblast (HDF) co-culture was used to investigate inflammatory cytokine/chemokine secretion upon pruritic/damaging IL-31/IL-33 stimulation, while autophagy signaling proteins were analysed by Western blot and immunofluorescence. IL-37 knock-in (KI) mice were bred for MC903-induced AD model. Ear swelling and EOS infiltration were assessed by H&E and immunohistochemical staining. Moreover, autophagy-related proteins in ear tissue were assessed. Snatching times were recorded to evaluate itching severity. Inflammatory cytokine/chemokine gene expression in lesional skin was assessed by QPCR. Serum cytokines and chemokines, and splenic regulatory T (Treg) cell were analysed by flow cytometry.
IL-37 significantly inhibited IL-6 and CXCL8 production, meanwhile upregulated autophagy-related LC3B and AMPK and down-regulated mTOR expression, implying IL-37 might reduce inflammation by inducing autophagy. However, no autophagy process was detected in either EOS or HDF alone culture, suggesting interaction between EOS and HDF is essential for autophagy mechanism in the resolution of allergic inflammation. Ear swelling of KI mice was reduced 10.8 and 15.3% at Day 15 and 17 comparing with wild type (WT) mice, respectively. EOS number in ear of KI was significantly lower than that of WT mice. Importantly, IL-37 significantly ameliorated the itching sensation, which is an intolerable clinical feature of AD. The LC3B and AMPK protein expressions were significantly increased, while p62 and mTOR expressions were significantly decreased in ear of KI compared with WT mice. QPCR results show that AD-related TNF-, IL-17A and CCL5 gene expression were higher in WT than that in KI mice. AD-related cytokine and chemokine levels in serum of KI was much lower, while Treg cells in spleen of KI was much higher comparing with WT mice. Together with in vitro experiments, the above results therefore demonstrated that IL-37 could regulate immune response to ameliorate inflammation via autophagy mechanism.
IL-37 could significantly ameliorate MC903-induced AD symptom by inhibiting eosinophil infiltration as well as eosinophils-mediated allergic inflammation via autophagy mechanism. It suggests that IL-37 could be a promising anti-inflammatory agent for AD.
著者TH Hou, XY Sun, KL Hon, J Zhu, CW Lam, CK Wong
會議名稱Hong Kong Society for Immunology 2019 Annual General Meeting and Scientific Meeting
會議地點Hong Kong

上次更新時間 2020-26-05 於 12:12