Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.
【저자키워드】 Respiratory tract diseases, Interleukins, 【초록키워드】 Inflammatory diseases, Inflammation, Macrophage, Lymphocytes, innate immune response, Pneumonia, Influenza, disease severity, neutrophil, lung, Lung injury, in vitro, virus, pulmonary inflammation, chemokine, Bronchoalveolar lavage fluid, Stat1, respiratory viral infections, COVID-19 patients, Inflammatory response, administration, Concentration, MAPK, Pathways, therapeutic target, STAT3, Activation, pro-inflammatory cytokine, circulating, microenvironment, NF-κB signaling, Host, Effect, co-culture, transcriptomic, mitigate, shown, significantly, reduced, indicate, in viral, correlated, inhibiting, alleviate, biological processe, respiratory epithelial cell, anti-inflammatory property, co-cultured, counteract, 【제목키워드】 lung, therapeutic, respiratory viral infection, implication,