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，尽管可用于细胞发挥其多种功能的氧气有限。由于缺氧本身不是免疫细胞发挥功能的最佳状态，细胞会感知并适应环境中氧浓度的变化。低氧诱导因子-1（hypoxia inducible factor-1，HIF-1）是一种高度保守的核转录因子，它的激活在很大程度上实现了对低氧的适应性反应。在这项研究中，我们提供了直接的证据表明HIF-1作为一种负调节因子在炎症反应的控制中的作用。将HIF-1α缺陷的初始T细胞（CD 4 ^+ CD 45 Rb ^）转移<high>到免疫缺陷的Rag 2 KO小鼠中，诱发了更严重的结肠炎，其固有层中炎性细胞的积累高于野生型T细胞。在炎症组织中积累的HIF-1a缺陷型T细胞产生的炎性细胞因子与野生型T细胞相当，这表明在APAP肝炎的进展中参与了未阐明的HIF-1介导但不依赖于腺嘌呤的机制。另一方面，T细胞中缺乏HIF-1 α基因的小鼠暴露于已知引起T细胞介导的肝炎的对乙酰氨基酚（APAP），导致与野生型小鼠相比更高的致死率。用抗CD 4中和抗体删除T细胞完全消除了突变小鼠中APAP诱导的死亡率，证实了T细胞参与了APAP诱导的肝炎。总的来说，这些结果表明，HIF-1抑制过度的炎症反应，从而作为一个负调节T细胞介导的免疫系统。需要进一步的研究来阐明HIF-1在调节T细胞功能中的重要分子机制，并将通过靶向氧传感和适应系统来开发新的炎症治疗策略。

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.