GPR174 Drives CD4+ T Cell Activation and Th17 Differentiation in Cardiopulmonary Inflammation During Heart Failure

Helper T17 (Th17) cells and Interleukin-17 (IL-17) are critical mediators of cardiac inflammation and heart failure (HF). G protein-coupled receptor 174 (GPR174), a receptor for lysophosphatidylserine (lysoPS) predominantly expressed in T lymphocytes, has been implicated in immune regulation and autoimmune diseases. Elevated levels of 18:0 lysoPS in the left ventricle following transverse aortic constriction (TAC) indicate its involvement in cardiac pathology. This study investigates the role of GPR174 in T cell differentiation and its contribution to cardiac inflammation and HF progression. Using genetically modified mouse models, we demonstrate that GPR174 deletion in CD4+ T cells (CD4-GPR174 KO), but not in CD8+ T cells, significantly alleviates TAC-induced mortality, cardiac dysfunction, pulmonary inflammation, and leukocyte infiltration. CD4-GPR174 KO mice exhibit reduced CD4+ T cell activation and a marked decrease in Th17 cell differentiation and IL-17 production in the lung and heart, with these changes being more pronounced than alterations in Th1 and Treg cells. Furthermore, TAC-induced dendritic cell activation and CD8+ T cell IFN-γ production are attenuated in CD4-GPR174 KO mice. Mechanistically, GPR174 deletion suppresses IL-17 expression and CD4+ T cell activation through the cAMP-PKA-CREB signaling pathway, as pharmacological inhibition of Protein Kinase A (PKA) or cAMP response element-binding protein (CREB) reverses these effects. These findings underscore the critical role of GPR174 in regulating CD4+ T cell differentiation and highlight its potential as a therapeutic target for mitigating cardiac inflammation and HF progression. Mechanism of PD1 on cardiac inflammation resolution during heart failure development Project Number: 5R01HL161085-03 Contact PI/Project Leader: CHEN, YINGJIE This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.