Plasmodium yoelii infection induces lung injury by modulating type 2 conventional dendritic cells autophagy via the STAT3-IRF4 signaling.

Malaria is an infectious disease caused by Plasmodium that severely impacts human health, often resulting in lung injury. Classical type 2 dendritic cells (cDC2) in the lungs play a crucial role in the pathogenesis of asthma and infectious diseases; however, their specific functions during Plasmodium infection remain poorly understood. In this study, we demonstrated a significant accumulation and activation of cDC2 in the lungs of mice infected with Plasmodium. While the phagocytosis ability of activated cDC2 decreases, it promotes the differentiation of CD4+ T cells towards Th1 cells, thereby exacerbating lung injury. During our investigation into cDC2 accumulation in the lungs, we discovered that this accumulation may occur through autophagy. Furthermore, mechanistic studies revealed that the effect of Plasmodium on cDC2 is mediated by the JAK/STAT3 signaling pathway. Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the influence of Plasmodium on cDC2. The role of cDC2 in lung injury induced by Plasmodium infection was further substantiated in IRF4-deficient mice infected with Plasmodium. In conclusion, our research significantly enriches our understanding of lung cDC2, further elucidates the pathogenic mechanisms of Plasmodium infection, and offers a novel theoretical foundation for malaria prevention and control. Schematic model demonstrated that Plasmodium infection suppressed autophagy in lung cDC2 via the TLR3/7-STAT3-IRF4 signaling pathway. Autophagy deficiency caused abnormal accumulation of cDC2 in lungs, impairing their phagocytosis capacity and clearance of malaria parasites. IL-12 secreted by cDC2 drove Th1-biased T-cell differentiation, which exacerbated pro-inflammatory responses and increased immunopathological damage in lung tissues. Inhibition of STAT3 or knockout of IRF4 within cDC2 restored cDC2 autophagy, reduced aberrant accumulation, re-established the phagocytic function of cDC2, and attenuated pro-inflammatory responses of Th1 cells, ultimately alleviating lung inflammatory damage.