IL‐37 Mitigates the Inflammatory Response in Macrophages Induced by SARS‐CoV‐2 Omicron Infection Through the NF‐κB Signaling Pathway

The expression levels of macrophage-associated cytokines are significantly greater in COVID-19 patients than in healthy individuals. Exploring strategies to modulate pathological cytokine storms can effectively prevent the development of severe coronavirus infection-induced pneumonia. Treatment with interleukin-37 (IL-37), an anti-inflammatory factor, has unique anti-inflammatory and antiviral effects on infections caused by various pathogens. In this study, we investigated the effect of IL-37 treatment on the SARS-CoV-2 Omicron-infection induced inflammatory response and its molecular mechanism. Our results demonstrated that IL-37 treatment effectively alleviated symptoms, reduced viral loads, suppressed the production of proinflammatory cytokines and chemokines both systemically (in serum) and locally (in the lungs), and attenuated lung lesions and inflammatory cell infiltration in Omicron-infected mice. The suppressed proinflammatory factors were macrophage-related, particularly CCL3 and CCL4, which were significantly inhibited. Furthermore, treatment with IL-37 significantly reduced the proportion of M1-type macrophages in lungs of Omicron-infected mice. In addition, we found that IL-37 targeted M1 macrophages through modulation of the NF-κB signaling pathway to suppress the production of proinflammtory factors during Omicron infection. This study elucidated the anti-inflammatory effect of IL-37 treatment on the Omicron-induced inflammatory response while identifying its specific target site, thereby providing fundamental insights for exploring potential clinical therapeutic interventions.