Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, United States.
College of Veterinary Medicine, Mississippi State University, Starkville, MS, United States.
Front Immunol. 2023 Jul 31;14:1224102. doi: 10.3389/fimmu.2023.1224102. eCollection 2023.
There are overwhelming reports on the promotional effect of hypoxia on the malignant behavior of various forms of cancer cells. This has been proposed and tested exhaustively in the light of cancer immunotherapy. However, there could be more interesting functions of a hypoxic cellular micro-environment than malignancy. There is a highly intricate crosstalk between hypoxia inducible factor (HIF), a transcriptional factor produced during hypoxia, and nuclear factor kappa B (NF-κB) which has been well characterized in various immune cell types. This important crosstalk shares common activating and inhibitory stimuli, regulators, and molecular targets. Impaired hydroxylase activity contributes to the activation of HIFs. Inflammatory ligands activate NF-κB activity, which leads to the expression of inflammatory and anti-apoptotic genes. The eventual sequelae of the interaction between these two molecular players in immune cells, either bolstering or abrogating functions, is largely cell-type dependent. Importantly, this holds promise for interesting therapeutic interventions against several infectious diseases, as some HIF agonists have helped prevent immune-related diseases. Hypoxia and inflammation are common features of infectious diseases. Here, we highlighted the role of this crosstalk in the light of functional immunity against infection and inflammation, with special focus on various innate and adaptive immune cells. Particularly, we discussed the bidirectional effects of this crosstalk in the regulation of immune responses by monocytes/macrophages, dendritic cells, neutrophils, B cells, and T cells. We believe an advanced understanding of the interplay between HIFs and NF-kB could reveal novel therapeutic targets for various infectious diseases with limited treatment options.
有大量报告表明，缺氧对各种形式的癌细胞的恶性行为具有促进作用。这已经在癌症免疫治疗中得到了充分的提出和验证。然而，缺氧细胞微环境的功能可能比恶性肿瘤更为有趣。缺氧诱导因子（HIF）是一种在缺氧时产生的转录因子，它与核因子 kappa B（NF-κB）之间存在着高度复杂的相互作用，这种相互作用在各种免疫细胞类型中已经得到了很好的描述。这种重要的相互作用共享共同的激活和抑制刺激物、调节剂和分子靶点。羟化酶活性的损伤导致 HIFs 的激活。炎症配体激活 NF-κB 活性，导致炎症和抗凋亡基因的表达。最终，这两种分子在免疫细胞中相互作用的后果，无论是增强还是削弱功能，在很大程度上取决于细胞类型。重要的是，这为针对几种传染病的有趣治疗干预提供了希望，因为一些 HIF 激动剂有助于预防免疫相关疾病。缺氧和炎症是传染病的共同特征。在这里，我们根据抗感染和炎症的功能免疫，特别关注各种先天和适应性免疫细胞，强调了这种相互作用的作用。特别是，我们讨论了这种相互作用在单核细胞/巨噬细胞、树突状细胞、中性粒细胞、B 细胞和 T 细胞中调节免疫反应的双向作用。我们相信，对 HIFs 和 NF-kB 之间相互作用的深入了解，可以为各种具有有限治疗选择的传染病揭示新的治疗靶点。
