Low Glucose plus β-Hydroxybutyrate Induces an Enhanced Inflammatory Response in Yak Alveolar Macrophages via Activating the GPR109A/NF-κB Signaling Pathway

• Published in: International journal of molecular sciences 2023-07, Vol.24 (14), p.11331
• Main Authors: Qi, Jiancheng, Yang, Qiyuan, Xia, Qing, Huang, Fangyuan, Guo, Hongrui, Cui, Hengmin, Xie, Yue, Ren, Zhihua, Gou, Liping, Cai, Dongjie, Kumbhar, Maqsood Ahmed, Fang, Jing, Zuo, Zhicai
• Format: Article
• Language: English
• Subjects: China; Cultural heritage; Cytokines; Dextrose; Genetic research; Glucose; Health aspects; Interleukins; low glucose; Macrophages; Mortality; Pathogens; primary alveolar macrophages (AMs); pro-inflammatory response; Protein expression; Proteins; Respiratory diseases; Tumor necrosis factor-TNF; yak; β-hydroxybutyrate (BHB)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241411331

Yaks are often subject to long-term starvation and a high prevalence of respiratory diseases and mortality in the withered season, yet the mechanisms that cause this remain unclear. Research has demonstrated that β-hydroxybutyrate (BHB) plays a significant role in regulating the immune system. Hence, we hypothesize that the low glucose and high BHB condition induced by severe starvation might have an effect on the pro-inflammatory response of the alveolar macrophages (AMs) in yaks. To validate our hypothesis, we isolated and identified primary AMs from freshly slaughtered yaks and cultured them in a medium with 5.5 mM of glucose or 2.8 mM of glucose plus 1-4 mM of BHB. Utilizing a real-time quantitative polymerase chain reaction (RT-qPCR), immunoblot assay, and enzyme-linked immunosorbent assay (ELISA), we evaluated the gene and protein expression levels of GPR109A (G-protein-coupled receptor 109A), NF-κB p65, p38, and PPARγ and the concentrations of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and tumor necrosis factor (TNF)-α in the supernatant. The results demonstrated that AMs exposed to low glucose plus BHB had significantly higher levels of IL-1β, IL-6, and TNF-α ( < 0.05) and higher activity of the GPR109A/NF-κB signaling pathway. A pretreatment of either pertussis toxin (PTX, inhibitor of GPR109A) or pyrrolidinedithiocarbamic (PDTC, inhibitor of NF-κB p65) was effective in preventing the elevated secretion of pro-inflammatory cytokines induced by low glucose plus BHB ( < 0.05). These results indicated that the low glucose plus BHB condition would induce an enhanced pro-inflammatory response through the activation of the GPR109A/NF-κB signaling pathway in primary yak AMs, which is probably the reason why yaks experience a higher rate of respiratory diseases and mortality. This study will offer new insight into the prevention and treatment of bovine respiratory diseases.