Cytokine Signaling Protein 3 Deficiency in Myeloid Cells Promotes Retinal Degeneration and Angiogenesis through Arginase-1 Up-Regulation in Experimental Autoimmune Uveoretinitis

• Published in: The American journal of pathology Vol. 188; no. 4; pp. 1007 - 1020
• Main Authors: Chen, Mei, Zhao, Jiawu, Ali, Imran H.A., Marry, Stephen, Augustine, Josy, Bhuckory, Mohajeet, Lynch, Aisling, Kissenpfennig, Adrien, Xu, Heping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018
• Subjects: Animals; Arginase - antagonists & inhibitors; Arginase - genetics; Arginase - metabolism; Autoimmune Diseases - genetics; Bone Marrow Cells - metabolism; Inflammation - pathology; Macrophages - metabolism; Mice, Inbred C57BL; Myeloid Cells - metabolism; Neovascularization, Pathologic - metabolism; Neutrophils - metabolism; Retinal Degeneration - pathology; Suppressor of Cytokine Signaling 3 Protein - deficiency; Suppressor of Cytokine Signaling 3 Protein - metabolism; Up-Regulation - genetics; Uveal Diseases - genetics
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2017.12.021

The suppressor of cytokine signaling protein 3 (SOCS3) critically controls immune cell activation, although its role in macrophage polarization and function remains controversial. Using experimental autoimmune uveoretinitis (EAU) as a model, we show that inflammation-mediated retinal degeneration is exaggerated and retinal angiogenesis is accelerated in mice with SOCS3 deficiency in myeloid cells (LysMCre/+SOCS3fl/fl). At the acute stage of EAU, the population of infiltrating neutrophils was increased and the population of macrophages decreased in LysMCre/+SOCS3fl/fl mice compared with that in wild-type (WT) mice. Real-time RT-PCR showed that the expression of tumor necrosis factor-α, IL-1β, interferon-γ, granulocyte-macrophage colony-stimulating factor, and arginase-1 was significantly higher in the LysMCre/+SOCS3fl/fl EAU retina in contrast to the WT EAU retina. The percentage of arginase-1+ infiltrating cells was significantly higher in the LysMCre/+SOCS3fl/fl EAU retina than that in the WT EAU retina. In addition, bone marrow–derived macrophages and neutrophils from the LysMCre/+SOCS3fl/fl mice express significantly higher levels of chemokine (C-C motif) ligand 2 and arginase-1 compared with those from WT mice. Inhibition of arginase using an l-arginine analog amino-2-borono-6-hexanoic suppressed inflammation-induced retinal angiogenesis without affecting the severity of inflammation. Our results suggest that SOCS3 critically controls the phenotype and function of macrophages and neutrophils under inflammatory conditions and loss of SOCS3 promotes the angiogenic phenotype of the cells through up-regulation of arginase-1.