Regulation of immunity and inflammation by hypoxia in immunological niches

Abstract

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

“…Preclinical analyses support proposals that HIF-α HIs can be used for the treatment of other diseases, ranging from chronic inflammation and ischemia-reperfusion injury to fibrosis and maybe even cancer. 18,21,23,64,65 Although there are some reports on the selectivities of the HIs vs other human 2OG oxygenases, 25,66,67 their cellular and in vivo selectivities with consequent possible off-target effects are not well understood, delaying the translation to clinical application. In part, the lack of information on selectivity is due to the lack of widely available, suitable methods for assaying HI activity in cells.…”

“…18,19 A vast amount of preclinical investigations indicates that pharmacologic targeting of HIF hydroxylases is a novel treatment option for many other diseases, ranging from inflammatory bowel disease over ischemic heart conditions to kidney inflammation and fibrosis. 18,[21][22][23][24] However, the underlying molecular mechanisms of the tissue-protective effect of hydroxylase inhibition are still not well understood. In preclinical studies, different hydroxylase inhibitors have been used, but their selectivity and possible HIF-independent off-target effects in cells are incompletely known and have not been comprehensively compared to each other.…”

Improving immune–vascular crosstalk for cancer immunotherapy

“…The impaired perfusion capacity of tumour blood vessels helps to create a highly hypoxic TME 22,25 . Hypoxia contributes to immunosuppression via several mechanisms (regulation of immunity by hypoxia is Reviewed in ref 37). First, hypoxia promotes the accumulation of myeloid-derived suppressor cells (MDSCs) and facilitates the differentiation and polarization of tumour-associated macrophages (TAMs) into an immunosuppressive M2-like phenotype 38–40 .…”

Mucosal inflammation downregulates PHD1 expression promoting a barrier‐protective HIF‐1α response in ulcerative colitis patients

“…5,21 Activation of hypoxiasensitive HIF-1 in these models, using prolyl hydroxylase inhibitors or genetic manipulation through PHD1 knockout, is protective through the promotion of intestinal epithelial barrier function and the suppression of mucosal immune cell activity. 22 HIF-2, on the contrary, promotes inflammatory responses. 9,23,24 While the impact of hypoxia on the inflammatory response has been extensively studied, much less attention has been paid to how inflammation regulates oxygen-sensing mechanisms and thereby determines the nature of the HIF-mediated adaptive hypoxic response.…”