Interleukin-10 Promotes Pathological Angiogenesis by Regulating Macrophage Response to Hypoxia during Development

Abstract

Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways.

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

“…In support of this idea is the observation that expression of IL-1␤, which was reported to sustain microglial activation and promote microvascular injury via the release of proapoptotic repulsive semaphoring 3A from neurons (68), was significantly reduced in the miR-155 Ϫ/Ϫ mouse retinas following OIR. Likewise, the levels of IL-10, which reduces endothelial cell proliferation in response to hypoxia (69), were diminished in the mutant mice. IL-10 deficiency in mice has been shown to significantly reduce pathological retinal angiogenesis (69).…”

“…Likewise, the levels of IL-10, which reduces endothelial cell proliferation in response to hypoxia (69), were diminished in the mutant mice. IL-10 deficiency in mice has been shown to significantly reduce pathological retinal angiogenesis (69). Not only did the combined deletion of CCN1 and miR-155 reverse these effects on IL-1 and IL-10, but it also strikingly increased the expression of IL-6, which further exacerbates neovascular growth (70).…”

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…The paradigm of M1 and M2 macrophages has been studied with respect to angiogenesis. [89][90][91][92] Classical activation generates M1 macrophages, which have proinflammatory functions as we have discussed, operative during inflammation in EAU and impart tissue destruction that is effectively neutralized via blocking TNF-alpha activity. Alternatively activated M2 macrophages confer responses related to wound healing, and are capable of generating VEGF and promoting angiogenesis.…”

Presence of Tumour-infiltrating FOXP3+Lymphocytes Correlates with Immature Tumour Angiogenesis in Renal Cell Carcinomas

“…As previously studied, Tregs play the immunosuppressive function through the secretion of some cytokines such as IL-10, IL-4, TGF-β, while the TGF-β may also act on tumour vascular pericytes and promote tumour angiogenesis (Gaengel et al, 2009). Recently, Dace et al (2008) found that IL -10 also promote pathological angiogenesis by regulating macrophage responses to hypoxia.…”