Background: T H 9 cells have emerged as important mediators of allergic airway inflammation. There is evidence that general control nonderepressible 2 (GCN2) affects the immune response under some stress conditions. However, whether GCN2 regulates CD4 1 T-cell differentiation during allergic inflammation remains unknown. Objective: We sought to clarify the regulatory roles of GCN2 in CD4 1 T-cell subset differentiation and its significance in patients with allergic airway inflammation. Methods: The effects of GCN2 in differentiation of T H cell subsets were detected by using the in vitro induction system. GCN2 knockout mice, ovalbumin-induced allergic airway inflammation, and adoptive transfer mouse models were used to determine the significance of GCN2 in T H 9 differentiation and allergic airway inflammation in vivo. RNA sequencing, real-time PCR, Western blotting, and other molecular approaches were used to identify the molecular mechanisms relevant to regulation of GCN2 in T H 9 cell differentiation.

Fatty acid binding protein 5 (FABP5) is mainly involved in the uptake, transport, and metabolism of fatty acid in the cytoplasm, and its role in immune cells has been recognized in recent years. However, the role of FABP5 in macrophage inflammation and its underlying mechanisms were not fully addressed. In our study, the acute liver injury and sepsis mouse models were induced by i.p. injection of LPS and cecal contents, respectively. Oleic acid (0.6 g/kg) was injected four times by intragastric administration every week, and this lasted for 1 wk before the LPS or cecal content challenge. We found that myeloid-specific deletion of FABP5 mitigated LPS-induced acute liver injury with reduced mortality of mice, histological liver damage, alanine aminotransferase, and proinflammatory factor levels. Metabolic analysis showed that FABP5 deletion increased the intracellular unsaturated fatty acids, especially oleic acid, in LPS-induced macrophages. The addition of oleic acid also decreased LPS-stimulated macrophage inflammation in vitro and reduced acute liver injury in LPS-induced or cecal content–induced sepsis mice. RNA-sequencing and molecular mechanism studies showed that FABP5 deletion or oleic acid supplementation increased the AMP/ATP ratio and AMP-activated protein kinase (AMPK) activation and inhibited the NF-κB pathway during the inflammatory response to LPS stimulation of macrophages. Inhibiting AMPK activation or expression by chemical or genetic approaches significantly rescued the decreased NF-κB signaling pathway and inflammatory response in LPS-treated FABP5-knockout macrophages. Our present study indicated that inhibiting FABP5 or supplementation of oleic acid might be used for the treatment of sepsis-caused acute liver injury.