Macrophage GPR18 signaling activation by Resolvin D2 mediates metabolic switch and cardiac repair after myocardial infarction.

Abstract

Abstract Higher inflammatory response is a major cause of heart failure and mortality post myocardial infarction (MI), a major health problem worldwide. Resolution of inflammation, well established as an actively orchestrated programmed response, is mediated by specialized pro-resolving lipid mediators (SPM) and cellular processes like efferocytosis. Resolvin D2 (RvD2), one such potent SPM, is expressed in leukocytes and stimulates the resolution of inflammation through signaling by its receptor GPR18. RvD2 signaling attenuates inflammation in immune-related conditions through macrophage (Mφ) cell-intrinsic and extrinsic mechanisms. The therapeutic potential of SPM has been demonstrated in treatment of sepsis and arthritis. However, the role of Mφ RvD2-GPR18 signaling in heart post-MI has not been elucidated. Here, we demonstrate (i) induction of GPR18 receptor on cardiac Mφ, (ii) >50% reduction in survival of myeloid- and Mφ-specific GPR18-/- mice, (iii) reduced heart function in GPR18-/- mice post-MI, (iv) a GPR18-dependent suppression of TLR4 signaling cytokines, and (v) suppression of TLR4-induced glycolytic metabolism by RvD2-GPR18 signaling in vitro in Mφ from human GPR18 chimeric adult mice. To summarize, our data suggest GPR18-dependent metabolic and phenotype switch to anti-inflammatory Mφ and cardiac repair post-MI. Further interrogation will delineate the intracellular pathways downstream of GPR18 and demonstrate the potential of RvD2 in reducing mortality post-MI.