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.

白细胞介素38最近被证明在肺炎性疾病中具有抗炎特性。然而，IL-38在病毒性肺炎中的作用仍然未知。在本研究中，我们证明流感和COVID-19患者的循环IL-38浓度与IL-36α显着增加，并且IL-38和IL-36α的水平分别与疾病的严重程度和炎症呈负相关和呈正相关。 。在体外培养的具有巨噬细胞的人类呼吸道上皮细胞共培养物中，以模拟肺微环境，IL-38能够通过抑制多聚（I：C）诱导的过炎性细胞因子和趋化因子通过细胞内STAT1，STAT3的过量产生来减轻炎症反应，p38 MAPK，ERK1 / 2，MEK和NF-κB信号通路。有趣的是 转录组分析显示，IL-38靶向基因与宿主对病毒的先天免疫反应有关。我们还发现，IL-38抵消了IL-36α在共培养物中诱导的生物学过程。此外，重组IL-38的给药可以减轻多聚I：C引起的肺损伤，减少中性粒细胞和巨噬细胞在支气管肺泡灌洗液中的早期积累，淋巴细胞的活化，促炎性细胞因子和趋化因子的产生以及肺泡的通透性-上皮屏障。综上所述，我们的研究表明IL-38在预防聚（I：C）诱发的肺炎期间防止过度的肺部炎症中起关键作用，从而为呼吸道病毒感染的新型治疗靶标奠定了基础。