Neutrophil-derived IL-10 increases CVB3-induced acute pancreatitis pathology via suppressing CD8+T cell activation while increasing macrophage STAT3-IL-6 cascade.

Acute pancreatitis (AP) is a lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and specific treatments are lacking. An increase in Interleukin-10 (IL-10) in the early stage of AP patients is closely related to AP severity. In Coxsackievirus B3 (CVB3) induced murine AP model, we found early IL-10 increased viral replication and pancreatic inflammation, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during viral infection remains unknown. Here we show that CVB3 infection enhanced neutrophil infiltration and IL-10 expression in the pancreas at day3 post infection (p.i.). Neutrophils served as an important early source of pancreatic IL-10 at the initiation of infection. Day3 pancreas extracts (D3P) also induced bone-marrow derived neutrophils (BMneu) to secrete IL-10. Adoptive transfer of D3P-pretreated BMneu into IL-10 KO mice increased viral replication and pancreas histopathology, which effect was blunted by the absence of IL-10 in BMneu. Mechanically, IL-10+ neutrophil increased IL-10R1 expression on MΦs and activated STAT3-IL-6/IL-10 signaling cascade while decreased IL-12 and MHC II expression in MΦs, thus impairing IFN-γ+Granzyme B+CD8+T cell activation and viral clearance. Adoptive transferring infected mice with activated CD8+T cells 4 days p.i. attenuated viral load and AP pathology indicating an AP-protective effect. Our findings document a novel immunoregulatory function of neutrophils in acute CVB3 infection, in which neutrophil-derived IL-10 impairs anti-viral CD8+T activation, and amplifies intrapancreatic inflammation via activating MΦ STAT3-IL-6 signaling cascade. An IL-10-targeting option is suggested for the future treatment of viral AP.