Chronic IL-21 exposure reshapes pulmonary environment, elevating risk of respiratory diseases

Abstract Age-related pulmonary diseases pose a significant health burden, yet the underlying mechanisms remain poorly understood. This study investigates the role of interleukin-21 (IL-21) in driving age-associated changes in lung function and immune responses. Using both murine models and human samples, we demonstrate that IL-21 induces a pro-inflammatory state in the lungs, characterized by increased levels of key inflammatory cytokines including TNF-α, IL-6, IL-33, CXCL-10, and IL-18. IL-21 exposure also promoted cellular senescence, evidenced by upregulation of senescence-associated genes and increased frequencies of KLRG1-positive T cells. Notably, IL-21 treatment led to significant alterations in lung macrophage phenotype and function. We observed increased lipid accumulation in macrophages, accompanied by upregulation of lipid uptake receptors TREM-2 and CD36. These changes were associated with elevated TGF-β secretion, suggesting a potential mechanism for IL-21-induced pulmonary fibrosis. Furthermore, IL-21 exposure resulted in impaired antiviral responses, characterized by reduced MHC-II expression on macrophages and diminished IFN-α production in response to viral challenges. Importantly, aged mice exhibited a lung phenotype strikingly similar to that induced by IL-21 treatment in young mice, including increased inflammation, cellular senescence, and altered macrophage lipid metabolism. Furthermore IL-21 expression was found to be elevated in the lungs of Idiopathic pulmonary fibrosis (IPF) patients compared to controls. These findings suggest that age-related elevation of IL-21 levels may be a key driver of pulmonary dysfunction in the elderly. Graphical Abstract