Hypoxia inducible factor-1α is an important regulator of macrophage biology

Abstract

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and β subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

Keywords: Biology; Diseases; HIF-1α; Macrophage; Stability.

Graphical abstract

Fig. 1

Structure and regulation of hypoxia-inducible factor-1α (HIF-1α) stability. The stability of HIF-1α is regulated via proline hydroxylation modulated by prolyl hydroxylase domains (PHDs). Activated PHDs hydroxylate HIF-1α at its oxygen dependent degradation domain (ODDD), triggering its association with von hippel-lindau (VHL) protein E3 ligase complex and leading to ubiquitin–proteasome pathway-dependent degradation. Hypoxia increases protein stability of HIF-1α and promotes its nuclear translocation and accumulation. HIF-1α associates with transcriptional co-activators, such as cAMP-response element binding protein (CREB) binding protein (CBP) and p300; the efficient transcriptional complexes form in hypoxia response elements (HREs) to regulate gene expression.

Fig. 2

HIF-1α regulates atherosclerosis by targeting macrophage function. Activation of HIF-1α in inflammatory macrophages can increase the necrotic plaque area through miRNA-210 and miRNA-383-mediated adenosine triphosphate (ATP) exhaustion, thus promoting atherosclerosis progression. In contrast, HIF-1α induces netrin-1 and unc-5 netrin receptor b (Unc5b) expression in hypoxia and decreases macrophage migration, thereby alleviating atherosclerosis.

Fig. 3

HIF-1α participates in glucose metabolic reprogramming. HIF-1α induces glycolytic gene expression to promote glucose uptake, glycolysis, and tricarboxylic acid cycle (TCA cycle), thereby enhancing HIF-1α stability. Pyruvate dehydrogenase kinase isozyme 1 (PDK1) inhibits pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), thereby promoting switching from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lipopolysaccharide (LPS), an inflammation inducer, inhibits the TCA cycle and induces succinic acid, fumaric acid, citric acid, and itaconic acid accumulation, resulting in stabilization of HIF-1α. The tetramer pyruvate kinase M2 (PKM2) is primarily cytoplasmic and exhibits high pyruvate kinase activity, which can catalyze phosphoenolpyruvate to generate pyruvate. Dimeric PKM2 can translocate into the nucleus with high protein kinase activity, acting as a transcription factor to regulate downstream transcription. The toll-like receptor 4 (TLR4) signaling pathway stimuli, such as LPS, promote phosphorylation of PKM2 to maintain the monomer/dimer state. PKM2 monomer or dimer can form a complex with HIF-1α in the nucleus and significantly increase the transcriptional activity of HIF-1α.