Role of HIF-1 in the regulation of inflammatory responses through sensing alterations in microenvironments of immune cells

当炎症发生时，免疫细胞从氧合良好的血管迁移到缺氧的炎症部位，在那里它们调节炎症反应，尽管细胞可获得的氧气有限，无法发挥其多种功能。由于缺氧本身不是免疫细胞功能的最佳选择，细胞感知并适应其环境中氧浓度的变化。对缺氧的适应性反应主要是通过激活一个保守的核转录因子，缺氧诱导因子-1 （HIF-1）来实现的。在这项研究中，我们提供了HIF-1作为负调节因子在炎症反应控制中的作用的直接证据。将hif -1α-缺陷的初始T细胞（CD4^+CD45Rb^<高>）转移到免疫缺陷的Rag2 KO小鼠中，可引起严重的结肠炎，炎症细胞在固有层的积累高于野生型T细胞。炎症组织中积累的hif -1a缺陷T细胞产生的炎症细胞因子与野生型T细胞相当，这表明hif -1介导但不依赖于细胞因子的机制参与了apap -肝炎的进展。另一方面，将T细胞中缺乏HIF-1 α基因的小鼠暴露于对乙酰氨基酚（APAP）中，与野生型小鼠相比，死亡率更高。对乙酰氨基酚（APAP）已知会引起T细胞介导的肝炎。删除带有抗cd4中和抗体的T细胞完全消除了突变小鼠apap诱导的死亡，证实了T细胞参与apap诱导的肝炎。总之，这些结果表明HIF-1可以抑制过度的炎症反应，从而作为T细胞介导的免疫系统的负调节因子。HIF-1在T细胞功能调控中的重要分子机制有待进一步研究，并将为开发一种针对氧传感和适应系统的炎症治疗新策略提供启示。

When an inflammation occurs, immune cells migrate from well-oxygenated blood vessels to hypoxic inflamed sites, where they regulate inflammatory responses despite limited oxygen available for the cells to exert their diverse functions. As hypoxia itself is not optimal for immune cells to function, the cells sense and adapt to the alteration of oxygen concentrations in their environments. The adaptive responses to hypoxia are largely achieved by an activation of a well-conserved nuclear transcription factor, hypoxia inducible factor-1 (HIF-1). In this study, we provide direct evidence for role of HIF-1 as a negative regulator in the control of inflammatory responses. Transfer of HIF-1α-deficient naive T cells (CD4^+CD45Rb^<high>) into immunodeficient Rag2 KO mice evoked severer colitis with higher accumulation of inflammatory cells in lamina propria than that of wild type T cells. Accumulated HIF-1a-deficient T cells in the inflamed tissues produced inflammatory cytokines comparable to wild type T cells, suggesting an involvement of unraveled HIF-1-mediated but cytokine-independent mechanisms in the progression of APAP-hepatitis. On the other hand, exposure of mice lacking HIF-1 α gene in T cells to acetaminophen (APAP), which is known to cause T cell-mediated hepatitis, resulted in higher lethality compared to that of wild type mice. Deletion of T cells with anti-CD4 neutralizing antibody completely abolished the APAP-induced mortality in the mutant mice, confirming an involvement of T cells in APAP-induced hepatitis. Collectively, these results suggest that HIF-1 suppresses excessive inflammatory responses and thus serves as a negative regulator for T cell-mediated immune systems. Further investigation is needed to elucidate precious molecular mechanisms for roles of HIF-1 in the regulation of T cell functions, and will shed light on the development of a new therapeutic strategy for inflammation by targeting the oxygen sensing and adaptive systems.