RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization

Takashi Ueta, Kenji Ishihara, Shoji Notomi, Jong Jer Lee, Daniel E. Maidana, Nikolaos E. Efstathiou, Yusuke Murakami, Eiichi Hasegawa, Kunihiro Azuma, Tetsuya Toyono, Eleftherios I. Paschalis, Makoto Aihara, Joan W. Miller, Demetrios G. Vavvas

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Abstract

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4–activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.

Original languageEnglish
Pages (from-to)23705-23713
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number47
DOIs
Publication statusPublished - Jan 1 2019

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