Pathogenic Role of an IL-23/γδT17/Neutrophil Axis in Coxsackievirus B3–Induced Pancreatitis

Abstract

Coxsackievirus B is a common cause of viral myocarditis and pancreatitis. IL-17A is intensively involved in the pathogenesis of viral myocarditis. Whether IL-17A plays a role in Coxsackievirus B-induced pancreatitis, characterized by acinar cell destruction and immune infiltration, remains largely unknown. We found a significant, but transient, increase of IL-17A expression and gdT influx in the pancreas of C57BL/6J mice within 3 d following CVB3 infection. The pancreatic IL-17A was mainly produced by Vg4 gd T cells, to a lesser extent by CD4 + Th17 cells. IL-17A 2/2 and TCRd 2/2 mice both reduced their susceptibility to CVB3 infection and pancreatitis severity when compared with the wild-type mice, without altering viral load. mAb depletion of Vg4gd T cells significantly improved mice survival and pancreatic pathology via decreasing Th17 expansion and neutrophil influx into the pancreas compared with isotype-treated mice. Transfer of Vg4gd T cells from wild-type, but not IL-17 2/2 , mice reconstituted TCRd 2/2 mice to produce IL-17 and develop pancreatitis to the level of wild-type mice during CVB3 infection, indicating gd T IL-17A is required for the onset of viral pancreatitis. IL-23 was robustly induced in the pancreas within the first day of infection. Administration of exogenous rIL-23 to mice increased CVB3 pancreatitis through in vivo expansion of IL-17 + gdT17 cells at 12 h postinfection. Our findings reveal a key pathogenic role for early-activated gdT17 cells in viral pancreatitis via promoting neutrophil infiltration and Th17 induction. This IL-23/gdT17/neutrophil axis is critically involved in the onset of CVB3 pancreatitis and represents a potential treating target for the disease.

Interleukin‐17—A multifaceted cytokine in viral infections

“…Neutralization with anti‐IL‐17 monoclonal antibody suppressed viral replication and improved cardiac pathology, which suggests that IL‐17 could be a potential target for controlling CVB3 induced AVMC (Yuan et al, 2010 ). Another study on C57BL/6 J mouse model demonstrated the pathogenic role of IL‐17A in CVB3 mediated pancreatitis (Yan et al, 2019 ). In CVB3 patients, the virus induces differentiation of CD4 + T cells into Th17 cells by nucleoporin (Nup) 98 (Long et al, 2016 ).…”

Evolved to protect, designed to destroy: IL‐17‐producing γδ T cells in infection, inflammation, and cancer

“…γδT17 cells, in particular Vγ4 + , were critical for viral clearance and protecting mice by recruiting both neutrophils and NK cells, most likely through a CXCL1-dependent mechanism [76]. In contrast to flu, Vγ4-expressing γδT17 cells were shown to be pathogenic during coxsackievirus B virus by inducing acute pancreatitis via their production of IL-17 [77]. Similarly, γδT17 cells also had a pathogenic role in a hepatitis B viral infection model, whereby they induced recruitment of suppressive polymorphonuclear (PMN) cells, leading to CD8 + T-cell exhaustion [78].…”

Role of Interleukin-17 in Acute Pancreatitis

“…Yang demonstrated that IL-17 is increased in the early phase of SAP, confirming that the adaptor protein Card9 coordinates IL-17 to balance immune reactions in SAP pathogenesis ( 75 ). By activating the IL-23/IL-17/neutrophil axis, IL-17A exacerbates virus-induced AP ( 76 ). Thus, the combination of biomarkers will help clinicians develop and adjust the clinical treatment of AP.…”