Abstract
Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
Highlights
Hypoxia is evident in many pathological contexts, including chronic intestinal inflammation, commonly known as inflammatory bowel diseases (IBD) [1, 2]
We show that myeloid hypoxia-inducible factor (HIF)-α/ARNT heterodimers are required for efficient resolution of inflammation in a dextran sulfate sodium (DSS)-induced acute colitis murine model, and confirm that these effects are due to disruption of HIF-1α and HIF-2α signaling
ARNT protein abundance was assessed by western blot analysis of lysates from bone marrow-derived macrophages (BMDMs) cultured under either normoxic (21% O2) or hypoxic (0.5% O2) conditions for 24 h, at which time ARNT protein was significantly depleted in LysMCre;Arntfl/fl BMDMs (Figure 1B)
Summary
Hypoxia (low oxygen tension) is evident in many pathological contexts, including chronic intestinal inflammation, commonly known as inflammatory bowel diseases (IBD) [1, 2]. Healthy colon tissue exhibits O2 partial pressures ranging from ∼85 mmHg in intestinal crypts to
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