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

Chen, Mei; Zhao, Jiawu; Ali, Imran; Marry, Stephen; Augustine, Josy; Bhuckory, Mohajeet; Lynch, A.C.; Kissenpfennig, Adrien; Xu, Heping

doi:10.1016/j.ajpath.2017.12.021

Cited by 26 publications

(26 citation statements)

References 52 publications

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“…SOCS1 and SOCS3 expression is known to engage in inhibitory signals to mitigate microglial activation and prevent cell toxicity (Kimura et al, ; Baker et al, ; McCormick & Heller, ). Supporting evidence comes from a study where SOCS3 deficiency in myeloid cells exaggerated retinal degeneration and accelerated retinal angiogenesis in a murine model of uveoretinitis (Chen et al, ). In these mice, SOCS3‐deficient retinas demonstrated higher levels of pro‐inflammatory cytokines IL‐1β, TNF‐α, and IFN‐γ as well as angiogenic factors including VEGF‐A.…”

Section: Targeting Mononuclear Phagocytes In Retinal Degenerative Dismentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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Section: Targeting Mononuclear Phagocytes In Retinal Degenerative Dismentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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“…The Socs3 / mice served as WT control. The LysMCre-Socs3 / mice were obtained by crossbreeding Socs3 / mice with LysMCre mice (31). The Cx3cr1 gfp/gfp mice were provided by Steffen Jung (Weizmann Institute of Science, Rehovot, Israel).…”

Section: Methodsmentioning

confidence: 99%

“…Studies have shown that deletion of Socs3 in LysM + cells (LysMCre-Socs3 / ) did not affect microglia in normal conditions, yet enhanced the in ammatory response in the CNS in experimental autoimmune encephalomyelitis and increased demyelination (30). The in ammatory response in experimental autoimmune uveoretinitis was also exaggerated in LysMCre-Socs3 / mice accompanied by severe retinal degeneration and angiogenesis (31). The LysMCre-Socs3 / mice also developed more severe diabetic retinopathy compared with WT mice (32).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

Peñalva

Little

et al. 2020

Preprint

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BackgroundWe generated a mouse model of primary microglial dysfunction by deleting two negative immune regulatory genes, Cx3cr1 and Socs3 (in LysM+ cells). This study aimed to understand how primary microglial dysfunction impacts retinal neurons during aging.MethodsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout (DKO), LysMCre-Socs3fl/fl, Cx3cr1gfp/gfp and Socs3fl/fl mice were maintained up to 12 months. Eyes were collected and processed for immunohistochemistry of IBA-1, cone arrestin, secretagogin, PKCα and GABA. Brain microglia from DKO and WT mice were stimulated with LPS + IFNγ or IL4. The expression of TNFα, IL1β, IL6, iNOS, IL12p40, IL23p19, CCL2, CCL5, CXCL2, IL10, CD206 and Arg1 were examined by real-time RT-PCR and protein production was measured by Luminex assay. Retinal explants from C57BL/6J mice were co-cultured with microglia from DKO or WT mice for 24 h, after which the number of cone arrestin+ cells in retinal flatmount were quantified.ResultsIn 3–5 month old mice, the number of microglia in retinal ganglion cell layer (GCL) and inner plexiform layer (IPL) were comparable in all strains. The DKO mice had a significantly higher number of microglia in the outer plexiform layer (OPL) but significantly lower numbers of cone arrestin+, secretagogin+ and GABA+ cells compared to Socs3fl/fl and single KO mice. During aging, 57% of the DKO mice died before 12 months old. The 10–12 months old DKO mice had significantly highers number of microglia in GCL/IPL and OPL than age-matched Socs3fl/fl and single KO mice. The aged DKO mice developed retinal pigment epithelial (RPE) dysmorphology accompanied by subretinal microglial accumulation. The number of photoreceptors, bipolar cells (Secretagogin+ or PKCα+) and GABA+ amacrine cells was significantly lower in aged DKO mice compared to age-matched Socs3fl/fl and single KO mice. Microglia from DKO mice showed significantly higher levels of phagocytic activity and produced higher levels of TNFα, IL6, CCL2, CCL5, CXCL2 and CXCL10 compared to microglia from Socs3fl/fl mice. Co-culture of retinal explants with DKO microglia (pre-treated with LPS + IFNγ or IL4) significantly reduced cone photoreceptor survival.ConclusionsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp DKO mice displayed primary microglial dysfunction and developed age-related retinal microgliopathy characterized by aggragated microglial activation and multiple retinal neuronal and RPE degeneration.Trial registration: Not applicable. The article does not contain any results from human participants.

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“…35,36 Arg1 is an intracellular enzyme that inhibits the process of angiogenesis and endothelial cell function by modulating the activity of the nitric oxide synthase. 37 Further studies have shown that blocking the IL-12 receptor not only promotes the expression of proinflammatory gene in the hematoma region and hematoma region CD11b+ cells, but also affects the expression of IFN-γ, TNF-α, IL-4 and IL-13. In addition, our study also found that blocking the IL-12 receptor significantly reduced the proportion of the M1 macrophages and increased the proportion of the M2 macrophages in the hematoma area of rats with ICH.…”

Section: Dovepressmentioning

confidence: 99%

<p>Intracerebral Hemorrhage Induced Brain Injury Is Mediated by the Interleukin-12 Receptor in Rats</p>

Yue

Liu

Yan

et al. 2020

NDT

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Background: IL-12 inhibition of the endothelial cell functions and angiogenesis is mediated by the cross-talk between the lymphocyte and the endothelial cells, which plays a key role in inhibiting the process of angiogenesis in the eyeballs and in malignant tumors. Methods: We established the intracerebral hemorrhage (ICH) rat model, and IL-12 receptor beta monoclonal antibody was injected into the ICH rats. Western blot, immunofluorescence and RT-qPCR were used to detect the gene expression. Brain water content, EB staining, Garcia test, Beam walking test and wire hanging test were used to assess the injury of brain in ICH rats. Results: IL-12 gene was significantly increase in hematoma border tissue of ICH rats, and IL-12 protein mainly localized in monocytes. Anti-IL-12 treatment with IL-12 monoclonal antibodies could not only significantly decrease the brain water content and EB content in brain tissues of ICH rats, but also significantly increase the score of the Garcia, Beam balance and the Wire hanging test in ICH rats. Moreover, anti-IL-12 treatment significantly decrease the expression of pro-inflammatory gene, inflammatory gene, p-JAK2/JAK2 and p-STAT4/STAT4 protein, but significantly increase the expression anti-inflammatory gene and CD31 protein, and M2 macrophage ratio in hematoma border tissues of ICH rats. In vitro, rmIL-12 inhibited the tube formation of brain microvascular endothelial cells (BMVES) in BMVES and bone marrow-derived monocytes (BMDM) co-culture systems, but not work in a separately cultured BMVES system. In addition, Fedratinib not only reduced p-JAK2/JAK2 and p-STAT4/STAT4 protein expression in BMDM after treating with b-FGF and rmIL-12, but also significantly increased the tube formation of BMVES in BMVES and BMDM co-culture systems after treating with b-FGF and rmIL-12. Conclusion: Blockade of IL-12 receptor attenuated brain injury after ICH in rat by promoting angiogenesis, and the mechanism might be related to blocking IL-12 could inhibit M2 cell activation via the JAK2/STAT4 pathway.

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

Cited by 26 publications

References 52 publications

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

<p>Intracerebral Hemorrhage Induced Brain Injury Is Mediated by the Interleukin-12 Receptor in Rats</p>

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