New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, USA.
Eur J Immunol. 2013 Mar;43(3):655-66. doi: 10.1002/eji.201242765. Epub 2013 Jan 31.
Hypoxia-adenosinergic suppression and redirection of the immune response has been implicated in the regulation of antipathogen and antitumor immunity, with hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in antibacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis, we studied the function of I.1 isoform in T cells using mice with total I.1 isoform deficiency and mice with T-cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of proinflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest a previously unrecognized immunosuppressive role for the I.1 isoform in T cells during bacterial sepsis. We interpret these data as indicative that the activation-inducible isoform I.1 hinders the contribution of T cells to the antibacterial response by affecting M1/M2 macrophage polarization and microbicidal function.
缺氧-腺嘌呤能抑制和免疫反应的重定向已被牵涉到抗病原体和抗肿瘤免疫的调节中，其中缺氧诱导因子 1α（HIF-1α）起着主要作用。在这项研究中，我们研究了同工型 I.1 的作用，它是 HIF-1α 的一种定量较少的替代同工型，在抗菌免疫和脓毒症存活中发挥作用。通过使用盲肠结扎和穿刺模型的细菌腹膜炎，我们使用总 I.1 同工型缺乏的小鼠和 T 细胞靶向 I.1 敲低的小鼠研究了同工型 I.1 在 T 细胞中的功能。我们发现，I.1 同工型的基因缺失导致对脓毒症致死的抵抗力增强，外周血中的细菌负荷明显降低，M1 巨噬细胞极化增加，血清中促炎细胞因子水平升高，抗炎细胞因子 IL-10 水平明显降低。我们的数据表明，I.1 同工型在细菌性脓毒症期间在 T 细胞中具有先前未被认识到的免疫抑制作用。我们将这些数据解释为表明，激活诱导的同工型 I.1 通过影响 M1/M2 巨噬细胞极化和杀菌功能来阻碍 T 细胞对抗菌反应的贡献。
