Increased Protein Citrullination as a Trigger for Resident Immune System Activation, Intraretinal Inflammation, and Promotion of Anti-retinal Autoimmunity: Intersecting Paths in Retinal Degenerations of Potential Therapeutic Relevance
We present evidence that protein citrullination, a proinflammatory and immune system-activating posttranslational modification (PTM) of arginine residues mediated by peptidyl arginine deiminases (PADs), is elevated in mouse models of retinal degenerations. Together with the fact that the animal models that we investigated (and their human counterparts) exhibit also anti-retinal autoantibodies, we propose that retinal citrullination is an immunogenic trigger that activates the immune system both locally and systemically, contributing to disease pathogenesis. Consistent with this possibility, we show that PAD compromise reduces the severity of Mertk-related retinal degeneration. Thus, PAD inhibition may be as a potential treatment strategy for retinal degenerations.
KeywordsCitrullination Posttranslational protein modification Peptidyl arginine deiminase Immune system Autoimmunity Retinitis pigmentosa Age-related macular degeneration MERTK Disease pathogenesis Disease progression Treatment
We thank Dr. TJ Hollingsworth, PhD, UTHSC Neuroscience Imaging Facility, for technical assistance with the histology sections of the double KO mice. This work was supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, to the Duke Eye Center.
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