Role of G protein-coupled receptor 15 (GPR15) in T cell recruitment and function during viral myocarditis

• Applicant: Privatdozentin Dr. Diana Lindner
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540017296

Myocarditis is clinically and pathologically defined as an inflammatory disease of the myocardium. It is caused by non-infectious and infectious agents, whereof viral infection represents the most common entity of myocarditis. Its clinical course has a broad spectrum of outcomes, ranging from mild symptoms and complete recovery to cardiac dysfunction and dilated cardiomyopathy (DCM). DCM after acute viral myocarditis often arises due to sustained inflammation, predominantly caused by insufficient virus clearance and subsequent virus persistence in the cardiac tissue. Thus, virus elimination is an eminent step towards recovery for patients suffering from viral myocarditis. In mice, the intraperitoneal injection of Coxsackie-Virus B3 is a well-established model to promote the development of viral myocarditis. The G-protein-coupled receptor-15, first identified in 1997, is described as T cell homing receptor in the gut during colitis, where GPR15 appears to constitute a counter-regulator of inflammation. Knocking out GPR15 in mice led to an aggravation of inflammation during colitis, where the receptor acts as T cell homing receptor, especially for cytotoxic (TC) and regulatory (Treg) T cells. Since T-cell mediated immunity is associated with inflammatory diseases, we investigated the role of GPR15 in viral myocarditis. In experimentally induced myocarditis in mice, GPR15-deficiency leads to impaired recovery and delayed virus elimination probably caused by the eminent differences in the inflammatory response during the acute phase of myocarditis. We hypothesize that GPR15 is probably important for both: virus clearance and dampening immune response. The project aims to investigate whether (i) GPR15 enables the timed invasion of specific T cells to the heart, (ii) GPR15 is important for T cell function of during myocarditis, (iii) the adverse course of myocarditis is favoured by GPR15-deficiency in a certain T cell subtype, and (iv) favouring early T cell recruitment by overexpressing the ligand of GPR15 in WT mice promotes virus clearance and leads to improved cardiac function after myocarditis. The results obtained will lead to a deeper understanding of the function of GPR15 during viral myocarditis. They may help to identify key mechanisms during the acute phase that may contribute to a better understanding of the pathophysiology leading to the development of DCM after viral myocarditis.

• DFG Programme: Research Grants