Production of porcine TNFα by ADAM17-mediated cleavage negatively regulates porcine reproductive and respiratory syndrome virus infection

Porcine reproductive and respiratory syndrome virus (PRRSV) causes a series of inflammatory reactions in sites of infection, companied by the upregulation of key inflammatory factor TNF alpha. TNF alpha, which serves as a "master regulator" of inflammatory cytokine production, is mainly produced by macrophages at the early infection stage. Here, we showed that porcine alveolar macrophages produced a great amount of soluble TNF alpha upon PRRSV infection. Furthermore, we found that TNF alpha had great anti-PRRSV effect. Next, by using inhibitor and genetic modification methods, we addressed that porcine TNF alpha production was mediated by ADAM17. Lastly, we proved that the (78)Arg-Ser-Ser motif of porcine TNF alpha contained the essential information for efficient cleavage. Taken together, our findings provide the direct evidence that ADAM17 cleaves porcine TNF alpha, which represents a new view for identifying potential therapeutic targets in anti-PRRSV therapy.