Abstract
Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6Chigh monocyte population in the circulation. Additionally, cardiac interstitial fibrosis was not affected by neutrophil depletion, whereas Gr-1+ cells other than neutrophils increased cardiac fibrosis at day 21 p.i. by increasing cardiac expression of profibrotic cytokine TNF-α and TGF-β. Thus, Neutrophil function is most likely not essential for CVB3 control and peripheral neutrophils play dispensable role in the pathogenesis of acute myocarditis and pancreatitis during CVB3 infection. Whereas Gr-1+ cells other than neutrophils play a major role in limiting viral replication while promoting myocardial and pancreatic inflammatory injury and fibrosis.
Highlights
Viral myocarditis (VMC), an inflammatory condition of the myocardium associated with several viral infections, is a significant cause of sudden cardiac death (SCD) and an underlying cause of dilated cardiomyopathy (DCM) in young adults (Sagar et al, 2012; Biesbroek et al, 2015; Pollack et al, 2015)
We found that upon Coxsackievirus B3 (CVB3) infection, neutrophils were the first innate immune cells recruited to the myocardium and pancreas of mice in large numbers
Peripheral absence of Gr-1+ cells caused exacerbation of CVB3 replication and CVB3 disease, indicating that Gr-1+ cells, but not neutrophils play a major role in determine the resistance to CVB3 infection and the pathogenesis of viral myocarditis as well as cardiac fibrosis in BALB/c mice
Summary
Viral myocarditis (VMC), an inflammatory condition of the myocardium associated with several viral infections, is a significant cause of sudden cardiac death (SCD) and an underlying cause of dilated cardiomyopathy (DCM) in young adults (Sagar et al, 2012; Biesbroek et al, 2015; Pollack et al, 2015). During the early viremia phase when cardiac viral replication peaks on 3 day post infection (dpi), innate immune responses are crucial determinants of the severity of myocardial damage, and contribute to the development of chronic myocarditis and dilated cardiomyopathy. In murine model of CVB3 viral myocarditis, we and other groups observe an early and abundant mobilization and influx of neutrophils into the heart and the pancreas of mice following CVB3 infection as early as 2.5 dpi (Smilde et al, 2016). This mobilization is earlier than any other infiltrated innate cells. There is currently no report about the role of neutrophils in experimental CVB3 myocarditis and pancreatitis
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