Interleukin‐4 protects mice against lethal influenza and Streptococcus pneumoniae co‐infected pneumonia

Streptococcus pneumoniae co‐infection post‐influenza is a major cause of mortality characterized by uncontrolled bacteria burden and excessive immune response during influenza pandemics. Interleukin (IL)‐4 is a canonical type II immune cytokine known for its wide range of biological activities on different cell types. It displays protective roles in numerous infectious diseases and immune‐related diseases, but its role in influenza and S . pneumoniae (influenza/ S . pneumoniae ) co‐infected pneumonia has not been reported. In our study, we used C57BL/6 wild‐type (WT) and IL‐4‐deficient (IL‐4 −/− ) mice to establish co‐infection model with S . pneumoniae after influenza virus infection. Co‐infected IL‐4 −/− mice showed increased mortality and weight loss compared with WT mice. IL‐4 deficiency led to increased bacterial loads in lungs without altering influenza virus replication, suggesting a role of IL‐4 in decreasing post‐influenza susceptibility to S . pneumoniae co‐infection. Loss of IL‐4 also resulted in aggravated lung damage together with massive proinflammatory cytokine production and immune cell infiltration during co‐infection. Administration of recombinant IL‐4 rescued the survival and weight loss of IL‐4 −/− mice in lethal co‐infection. Additionally, IL‐4 deficiency led to more immune cell death in co‐infection. Gasdermin D (GSDMD) during co‐infection was induced in IL‐4 −/− mice that subsequently activated cell pyroptosis. Treatment of recombinant IL‐4 or inhibition of GSDMD activity by disulfiram decreased immune cell death and bacterial loads in lungs of IL‐4 −/− co‐infected mice. These results suggest that IL‐4 decreases post‐influenza susceptibility to S . pneumoniae co‐infection via suppressing GSDMD‐induced pyroptosis. Collectively, this study demonstrates the protective role of IL‐4 in influenza/ S . pneumoniae co‐infected pneumonia.