Myeloid GHSR Deficiency Protects Against Endotoxemia via Macrophage Mitochondrial Reprogramming

Background: Endotoxemia is a severe inflammatory condition that is characterized by acute immune responses and oxidative stress; endotoxemia can further develop into a cytokine storm and sepsis leading to severe organ damage. Our recent studies revealed that the growth hormone secretagogue receptor (GHSR) regulates macrophage polarization in obesity- and aging-associated chronic inflammation. However, its role in acute inflammation during endotoxemia remains unclear. Methods: We subjected myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsr^f/f) to lipopolysaccharide (LPS)-induced endotoxemia in vivo and treated bone marrow-derived macrophages (BMDMs) with LPS in vitro. Subsequently, mouse survival rate and inflammatory signatures in the blood, peritoneal cavity, liver, and BMDM were assessed. In the ex vivo study, conditioned medium (CM) from BMDMs was applied to primary hepatocytes to assess how BMDM-derived CM influences hepatocyte inflammatory responses. Results: Myeloid-specific Ghsr knockout mice exhibited a significantly improved survival rate following LPS-induced endotoxemia, accompanied by reduced systemic inflammation, evident in the blood, peritoneal macrophages, and liver. In addition, Ghsr deficiency suppressed LPS-induced caspase-1 activation and pro-inflammatory cytokine secretion in macrophages. Consistent with these results, conditioned media from Ghsr-deficient BMDMs attenuated the inflammatory responses of primary hepatocytes. Mechanistically, LPS increased GHSR expression in BMDMs, and Ghsr-deficient BMDMs activated mitochondrial respiration and suppressed production of mitochondrial reactive oxygen species (ROS), resulting in downregulation of inflammatory activation of macrophages following LPS exposure. Conclusions: These data demonstrate that macrophage GHSR promotes systemic and tissue inflammation during endotoxemia by regulating mitochondria-associated macrophage polarization. The findings suggest that macrophage GHSR may represent a promising immunomodulatory target for acute inflammatory states, including endotoxemia and sepsis.