Abstract
Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.
Highlights
Hypoxia-inducible factor (HIF) is a transcription factor that is composed of two basic helix-loop-helix proteins, α and β, which both belong to the PER-ARNT-SIM (PAS) family [1]
HIF binds to a pentanucleotide sequence (RCGTG) present in hypoxic response elements (HREs) that are carried by certain target genes
Recent studies of HIF-1α have highlighted the important role of sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) signaling for this migration phenotype [52,53,56,57,58]
Summary
Hypoxia-inducible factor (HIF) is a transcription factor that is composed of two basic helix-loop-helix proteins, α and β, which both belong to the PER-ARNT-SIM (PAS) family [1]. There are only two types of β subunits, aryl hydrocarbon receptor nuclear translocator (ARNT, known as HIF-1β) and ARNT2 The latter is expressed in the nucleus, is not responsive to oxygen, and has other functions in gene transcription [2,3,4,5,6]. Higher levels of S1P are present in affected tissues, thereby leading to greater signal input to macrophages from their environment [21]. Recent studies of HIF-1α have highlighted the important role of S1P/S1PR signaling for this migration phenotype [52,53,56,57,58]. In this review, HIF-1α and S1P/S1PR signaling in macrophages in response to inflammation in wound healing is presented, and insights into possible mechanisms are discussed
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