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

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-αto 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-βand 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.