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RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

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 RIP1^K45A/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.

SUBMITTER: Ueta T

PROVIDER: S-EPMC6876205 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

Ueta Takashi T Ishihara Kenji K Notomi Shoji S Lee Jong-Jer JJ Maidana Daniel E DE Efstathiou Nikolaos E NE Murakami Yusuke Y Hasegawa Eiichi E Azuma Kunihiro K Toyono Tetsuya T Paschalis Eleftherios I EI Aihara Makoto M Miller Joan W JW Vavvas Demetrios G DG

Proceedings of the National Academy of Sciences of the United States of America 20191104 47

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 ...[more]

PMID: 31685620

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Project description:ObjectivesMesenchymal stromal/stem cell (MSC)-based therapy has become a promising approach to periodontal tissue repair. Adipose-derived stromal/stem cells (ASCs), compared with other dental or non-dental MSCs, serve as promising candidates for MSC therapy due to non-invasive acquisition and abundant sources. This study aimed to explore the effects of ASC therapy in experimental periodontitis and the underlying mechanism.MethodsMicro-CT was performed to evaluate the alveolar bone parameters following local injection of ASCs. Immunohistochemistry and immunofluorescence were employed to detect the expression of IL-1β, osteocalcin (OCN), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and surface markers of macrophage polarization. Afterward, multiple reaction monitoring (MRM)-based targeted tryptophan metabolomic analysis was used to examine the ASC metabolites. Chromatin immunoprecipitation (ChIP)-qPCR assay was performed to investigate the direct binding of aryl hydrocarbon receptor (AhR) and NRF2.ResultsAlveolar bone loss was reduced, and the ratio of iNOS+/CD206+ macrophages was significantly decreased after ASC injection in the rat models of periodontitis. ASCs promoted NRF2 expression and activation in macrophages, while NRF2 silencing in macrophages blocked the regulation of ASCs on macrophages. Furthermore, the expression of indoleamine 2,3-dioxygenase (IDO) of ASCs in the inflammatory condition was high. The inhibitor of IDO, 1-methyltryptophan (1-MT), impaired the therapeutic effects of ASCs in experimental periodontitis and regulation of macrophage polarization. Mechanistically, kynurenine (Kyn), a metabolite of ASCs catalyzed by IDO, activated AhR and enhanced its binding to the promoter of NRF2, which stimulated M2 macrophage polarization.ConclusionsThese findings suggested that ASCs can alleviate ligature-induced periodontitis through modulating macrophage polarization by the IDO-dependent Kyn-AhR-NRF2 pathway, uncovering a novel mechanism and providing a scientific basis for ASC-based therapy in experimental periodontitis.

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RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

Publications

RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

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