TY - JOUR
T1 - RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization
AU - Ueta, Takashi
AU - Ishihara, Kenji
AU - Notomi, Shoji
AU - Lee, Jong Jer
AU - Maidana, Daniel E.
AU - Efstathiou, Nikolaos E.
AU - Murakami, Yusuke
AU - Hasegawa, Eiichi
AU - Azuma, Kunihiro
AU - Toyono, Tetsuya
AU - Paschalis, Eleftherios I.
AU - Aihara, Makoto
AU - Miller, Joan W.
AU - Vavvas, Demetrios G.
N1 - Funding Information:
This work was supported by the Yeatts Family Foundation (D.G.V.); Monte J. Wallace (D.G.V.); 2013 Macula Society Research Grant Award (to D.G.V.); a Physician Scientist Award (to D.G.V.); unrestricted grant from the Research to Prevent Blindness Foundation (to J.W.M. and D.G.V.); National Eye Institute (NEI) R21EY023079-01/A1 (to D.G.V.); NEI Grant EY014104 (Massachusetts Eye and Ear Infirmary Core Grant) (to D.G.V.); Loeffler Family Fund (D.G.V.); R01EY025362-01 (to D.G.V.); ARI Young Investigator Award (to D.G.V.); Foundation Lions Eye Research Fund (D.G.V.); NIH NEI Core Grant P30EY003790 (to D.G.V.); Agence National de la Recherche; ERA-Net for Research on Rare Diseases, Institut Universitaire de France (D.G.V.); and a fellowship from the TOYOBO Biotechnology Research Foundation (to T.U.). We also thank Fengyang Lei for technical input.
Funding Information:
ACKNOWLEDGMENTS. This work was supported by the Yeatts Family Foundation (D.G.V.); Monte J. Wallace (D.G.V.); 2013 Macula Society Research Grant Award (to D.G.V.); a Physician Scientist Award (to D.G.V.); unrestricted grant from the Research to Prevent Blindness Foundation (to J.W.M. and D.G.V.); National Eye Institute (NEI) R21EY023079-01/A1 (to D.G.V.); NEI Grant EY014104 (Massachusetts Eye and Ear Infirmary Core Grant) (to D.G.V.); Loeffler Family Fund (D.G.V.); R01EY025362-01 (to D.G.V.); ARI Young Investigator Award (to D.G.V.); Foundation Lions Eye Research Fund (D.G.V.); NIH NEI Core Grant P30EY003790 (to D.G.V.); Agence National de la Recherche; ERA-Net for Research on Rare Diseases, Institut Universitaire de France (D.G.V.); and a fellowship from the TOYOBO Biotechnology Research Foundation (to T.U.). We also thank Fengyang Lei for technical input.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075259584&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075259584&partnerID=8YFLogxK
U2 - 10.1073/pnas.1908355116
DO - 10.1073/pnas.1908355116
M3 - Article
C2 - 31685620
AN - SCOPUS:85075259584
SN - 0027-8424
VL - 116
SP - 23705
EP - 23713
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -