Abstract
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.
Highlights
Virus lung infections represent a considerable global health burden, as recognized by WHO’s Battle against Respiratory Viruses initiative[1]
The primary cells being infected during viral infection are respiratory epithelial cells, and the interaction of respiratory epithelial cells with macrophages of barrier organs constitute the first line of defense against viral pathogens[28]
We investigated whether IL-38 pathways could modulate immunopathology during viral pneumonia in vitro by firstly evaluating the cytokine production in the coculture thereafter
Summary
Virus lung infections represent a considerable global health burden, as recognized by WHO’s Battle against Respiratory Viruses initiative[1]. Most patients who died in the outbreak of severe acute respiratory syndrome (SARS) in 2003, as well as Coronavirus disease 2019 (COVID-19) that is currently pandemic, developed ARDS, septic shock, Pathological studies showed that imbalanced host immune response to viral pathogenicity contributed to the fatal lung injury in respiratory viral infection, characterized by high viral load, excessive cytokines expression, and overwhelming immune cells influx[5,6]. Gao et al Cell Death and Disease (2021)12:53 targets for personalized immunotherapy in acute lung inflammation caused by a respiratory virus. A combination of antiviral therapy and anti-inflammatory non-steroidal inhibiting cyclooxygenases (COX) has been shown to improve the survival of mice infected with influenza A/H5N1 virus[6].
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