Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma

Abstract

We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/ SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3 + eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4 + CRTH2 + Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.

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

“…Moreover, IL-37b Tg mice with or without AD showed a significantly lower expression of CCL2 ( Figure 2G) and higher expression of Foxp3 ( Figure 3F). Similar to our previous published results (49), the present findings further confirmed IL-37b could suppress innate immunity via the reduction of the infiltration of eosinophils and induction of Foxp3+ Treg cells, probably by regulating intestinal metabolites.…”

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

“…These findings suggest that coordination between CCL28-CCR10 chemokine signaling and the p38 MAPK pathway has important implications for reprogramming of epithelial cells, a speculation that warrants further investigation. Second, POU2AF1 encodes a transcriptional coactivator that regulates B cell maturation and humoral immunity and is expressed in both airway epithelial and B cells [51,52]. A prior study using IPF lungs documented that transcriptome analysis identified POU2AF1 as a promoter of pulmonary fibrosis and it is highly expressed in aggregates of B cells [53].…”

Mimicking Antigen-Driven Asthma in Rodent Models—How Close Can We Get?

“…This causes a protracted experimental window up to several months and in some cases, due to the continuous exposure to the allergen, leads to tolerance in the mice (96)(97)(98)(99)(100)(101). The transgenic technology allowed the generation of mice with characteristics of chronic asthma and airway remodeling (102,103). Furthermore, transgenic models allowed the identification of an important migration factor of DCs to the lung (104) and the role of IL-33 receptor suppressor of tumorigenicity 2 (ST2) in development of chronic asthma in mice by regulating ILC2s, mast cells, IL9 and IL-13 in the lungs (105).…”