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

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.

Current Understanding of IL-37 in Human Health and Disease

“…The serum concentration of involucrin, a keratinizing epithelia protein, in AD patients is significantly higher than that of HCs, which is related to the insufficiency of IL-37 (53). IL-37b suppresses the production of pro-inflammatory cytokines and chemokines in AD, increases autophagosome LC3B protein biogenesis and reduces the ubiquitinated protein p62 associated with autophagy through the activation of AMPK and the inhibition of mTOR (54). In CRISPR/Cas9 human IL-37b knock-in mice, IL-37b significantly alleviates the MC903induced swelling of the ear tissue and itching sensation, reduced the circulating IL-6 and in situ inflammation, decreases eosinophil infiltration in the ear lesion, and significantly upregulates Foxp3+ regulatory T cells (Treg) in ear and spleen (54).…”

“…IL-37b suppresses the production of pro-inflammatory cytokines and chemokines in AD, increases autophagosome LC3B protein biogenesis and reduces the ubiquitinated protein p62 associated with autophagy through the activation of AMPK and the inhibition of mTOR (54). In CRISPR/Cas9 human IL-37b knock-in mice, IL-37b significantly alleviates the MC903induced swelling of the ear tissue and itching sensation, reduced the circulating IL-6 and in situ inflammation, decreases eosinophil infiltration in the ear lesion, and significantly upregulates Foxp3+ regulatory T cells (Treg) in ear and spleen (54). Furthermore, IL-37b restores the gut microbiota diversity by the enhancement of autophagy mediated by microbiota metabolites though the regulation of the AMPK-mTOR signaling pathway (54).…”

“…In CRISPR/Cas9 human IL-37b knock-in mice, IL-37b significantly alleviates the MC903induced swelling of the ear tissue and itching sensation, reduced the circulating IL-6 and in situ inflammation, decreases eosinophil infiltration in the ear lesion, and significantly upregulates Foxp3+ regulatory T cells (Treg) in ear and spleen (54). Furthermore, IL-37b restores the gut microbiota diversity by the enhancement of autophagy mediated by microbiota metabolites though the regulation of the AMPK-mTOR signaling pathway (54). Thence, IL-37b can significantly reduce allergic inflammation mediated by eosinophils, as well as the diversity of intestinal bacteria and their metabolites in AD through the regulation of autophagy, revealing a potential therapeutic strategy against AD.…”

Skewed inflammation is associated with aberrant interleukin‐37 signaling pathway in atopic dermatitis

“…Therefore, the optimal production and activities of IL‐37 are crucial in maintaining the homeostasis of the immune system and response. We have recently elucidated the IL‐37‐mediated novel intracellular mechanisms for the regulation of the activation of eosinophils, principal effector cells of allergic inflammation, in an AD murine model 11 . Therefore, we herein hypothesized that IL‐37 is a physiological inhibitor of allergic inflammation via suppressing eosinophil‐related signaling pathways in AD patients.…”

“…We have recently elucidated the IL-37-mediated novel intracellular mechanisms for the regulation of the activation of eosinophils, principal effector cells of allergic inflammation, in an AD murine model. 11 Therefore, we herein hypothesized that IL-37 is a physiological inhibitor of allergic inflammation via suppressing eosinophil-related signaling pathways in AD patients. Since the expression of IL-37 receptors on the immune effector cells has not been reported in AD patients, the detailed mechanism involved in the anti-inflammatory role of IL-37 in regulating the allergic inflammation and immune response in AD patients remains elusive.…”