IL-36R deletion mitigates cigarette smoke-induced airway inflammation and skeletal muscle dysfunction.

Abstract

Chronic inflammation is a crucial driver in the development of chronic obstructive pulmonary disease (COPD) and its comorbidities, such as skeletal muscle dysfunction. Heightened IL-36 expression in the lung and systemic circulation has been observed in patients with COPD, but the potential role of IL-36 in COPD still needs further exploration. Herein, we established a COPD model through long-term cigarette smoke (CS) exposure in mice with or without IL-36R deletion. Elevated IL-36 cytokines were observed in the lung and peripheral blood of CS-exposed wild-type mice. IL-36R gene deficiency attenuated CS-induced lung parenchymal destruction and airway inflammation, as evidenced by decreased secretion of inflammatory mediators, such as IL-6, IL-1β, TNF-α and MMP9, and a diminished Th1/Tc1- and Tfh-biased immune response. In addition, skeletal muscle dysfunction was alleviated in CS-exposed mice by IL-36R deletion. Further investigations indicated that CS treatment induced the expression of IL-36 cytokines and IL-36R in C2C12 myotubes and skeletal muscles, and that IL-36 cytokines could upregulate FBXO32 and TRIM63 expression by activating NF-κB p65 pathway, thereby leading to skeletal muscle atrophy in an endocrine and autocrine/paracrine manner. Our findings provide evidence for a critical role of the IL-36/IL-36R signaling in the pathogenesis of CS-induced COPD and comorbid skeletal muscle dysfunction.