Hypoxia and Inflammation: Insights From High-Altitude Physiology

Abstract

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

Keywords: high altitude; hypoxia; hypoxia inducible factor; inflammation; nuclear factor-κB.

Figure 1

Hypoxia inducible factor (HIF)-nuclear factor (NF)-kappa B (NF-κB) crosstalk. In normoxic conditions, prolyl hydroxylases (PHDs) hydroxylate HIF-α and the IKKβ subunit of the IκB kinase (IKK) complex, marking them for degradation and thereby reducing transcriptional activity of HIF and repressing (but not completely blocking) NF-kB activity. In hypoxia, PHD activity decreases since it utilizes oxygen as a cofactor. Therefore, HIF-α is stabilized and can dimerize with the constitutively active HIF-β subunit. The complex translocates to the nucleus to upregulate expression of genes involved in the hypoxia response. In hypoxia, with reduced PHD activity, the rate of IKK degradation of IκB increases, releasing repression of NF-κB and allowing it to translocate to the nucleus at higher rates and upregulate inflammatory gene expression. PHD, prolyl hydroxylase; HIF, hypoxia-inducible factor; NF-κB, Nuclear factor kappa B; IKK, IκB kinase complex (composed of IKK-α, IKK-β, and IKK-γ subunits); and IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor.

Figure 2

Predicted contributions of inflammation to high-altitude illnesses, erythrocytosis, and immune function. Hypoxic conditions lead to increases in pro-inflammatory mediators, which may play a role in the development of high-altitude illnesses [(Acute Mountain Sickness (AMS), high-altitude pulmonary hypertension (HAPH), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE)] and erythrocytosis, or modify immune function. (1) Julian et al. (2011); (2) Liu et al. (2017); (3) Wang et al. (2018); (4) Varatharaj and Galea (2017); (5) Wilkins et al. (2015); (6) Brito et al. (2020); (7) Mishra et al. (2016); (8) Song et al. (2016); (9) Zhou et al. (2017); (10) Jackson et al. (2010); (11) Liao et al. (2018); (12) Bennett et al. (2019); (13) Imagawa et al. (1990); (14) Haase (2013); (15) Kvamme et al. (2013); (16) Baze et al. (2011); (17) Facco et al. (2005); and (18) Feuerecker et al. (2019).