Hypoxic Influences on Myeloid Cells during Inflammation and Inflammation-Associated Cancer

Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. This body of work investigates the role of myeloid HIF-αs in the settings of several acute and chronic inflammatory diseases. First, the role of pan-HIF signaling in acute intestinal inflammation is investigated by depleting myeloid ARNT, the obligate heterodimeric binding partner for both HIF-α subunits, in a dextran sodium sulfide-induced murine acute colitis model. Myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and monocytes into inflamed colon. 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. These data suggest that myeloid HIF signaling promotes the effective resolution of acute colitis. Second, the effect of HIF inhibition in colitis-associated cancer (CAC) and other inflammatory diseases is studied using myeloid-specific depletion of each HIF-α subunit or panHIF. Myeloid HIF deficiency elevates tumor burden and advances disease progression of murine CAC. Acute skin inflammation is slightly mitigated upon loss of myeloid ARNT. However, myeloid HIFs are dispensable for leukocyte influx in a peritonitis model and animal survival in an endotoxemia model. Collectively, these data suggest that HIF-αs adopt diverse roles during inflammation, and their functions highly depend on specific types and stages of disease