Ghrelin Receptor Regulates Neuro-inflammation in Aging through Macrophage Polarization
Hongying Wang1,2,*, Chia-Shan Wu1,*, Sunja Kim3, Jianrong Li3, Xiaoqiu Xiao2, Hui Zheng4, Yuxiang Sun1, 4, 5
1Department of Nutrition and Food Science, Texas A&M University, College Station; 2Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 3Department of Veterinary Integrative Biosciences, Texas A&M University, College Station; 4Huffington Center on Aging, Baylor College of Medicine, Houston; 5Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston.
Aging is commonly associated with systemic low-grade inflammation, which is closely linked to insulin resistance, metabolic and cognitive impairments. Ghrelin is the only circulating orexigenic hormone known to increase obesity and insulin resistance. We have reported roles of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), in energy metabolism, insulin resistance and adipose tissue inflammation, showing that old Ghsr-/- mice exhibit a lean and insulin-sensitive phonotype. Macrophages are major mediators of inflammation and lipid metabolism. We have also found that the expression of GHS-R in macrophages increases with age, and GHS-R global ablation promotes anti-inflammatory macrophage polarization, attenuating inflammation in adipose tissue and liver in aging mice. The peritoneal macrophages of old Ghsr-/- mice show reduced pro-inflammatory cytokine expression, reduced M1/M2 macrophage ratio, and produce more norepinephrine, which indicates a shift in macrophage polarization towards anti-inflammatory state. To further explore the cell-autonomous role of GHS-R in macrophages, we generated myeloid-specific GHS-R deficient mice. The myeloid-specific GHS-R deletion attenuates lipopolysaccharide (LPS)-induced inflammation, both in vivo and in ex vivo cultures of peritoneal macrophages. Furthermore, suppression of GHS-R signaling in bone marrow-derived macrophages exerts anti-inflammatory effect in LPS-induced inflammation. More importantly, we find that myeloid-specific GHS-R deletion reduces neuro-inflammation and expression of Alzheimer's disease (AD) marker genes under diet-induced obesity. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization, and suggest that myeloid GHS-R may have important roles in neuro-inflammation in AD.