1. Figure 2 The hypoxia-induced proinflammatory
response versus the adaptive response in various cell types
Figure 2 | The hypoxia-induced proinflammatory response versus the adaptive response in various cell types. a | Hypoxia increases the survival of myeloid cells and their expression of proinflammatory cytokines, including TNF, which increases epithelial permeability through the deregulation of tight junction (TJ) proteins. In addition, epithelial cells become apoptotic as hypoxia persists, which further contributes to the disruption of barrier integrity. Besides proinflammatory cytokines, macrophages release the pro-angiogenic factor vascular endothelial growth factor A (VEGFA) under hypoxic conditions. Hypoxia-exposed endothelial cells are also pro-thrombogenic, upregulate expression of cell-adhesion molecules and secrete proinflammatory mediators, which attract immune cells, and increase their adhesion and extravasation. b | Intestinal epithelial cells adapt to the local physiological hypoxic state through the increased expression of barrier protective proteins and receptors involved in adenosine signalling while concomitantly downregulating the expression of adenosine transporters. These proteins can also all be induced by butyrate, released by gut bacteria, which thereby increases gut barrier integrity. In addition, they prevent neutrophil migration into the mucosa via the release of netrin-1 and enhance apical neutrophil shedding by upregulating the expression of CD55. Antimicrobial peptides are produced. In addition to the epithelium, endothelial cells and dendritic cells (DCs) also exhibit increased expression of the adenosine receptors. Downregulation of adenosine transporters has also been demonstrated on endothelial cells in response to hypoxia. A2BR, adenosine receptor A2B; CCL20, C–C motif chemokine 20; CXCL2, C–X–C motif chemokine 2; CD, cluster of differentiation; ENT, equilibrative nucleoside transporter; FADD, FAS-associated death domain protein; ITF, intestinal trefoil factor; MDR1, multidrug resistance protein 1; PAF, platelet activating factor; PG, prostaglandin; TM, thrombomodulin; TREM1, triggering receptor expressed on myeloid cells.
Van Welden, S. et al. (2017) Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD
Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro