Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis

• Published in: Disease models & mechanisms Vol. 6; no. 2; pp. 467 - 478
• Main Authors: Moscarello, Mario A, Lei, Helena, Mastronardi, Fabrizio G, Winer, Shawn, Tsui, Hubert, Li, Zhen, Ackerley, Cameron, Zhang, Li, Raijmakers, Reinout, Wood, D Denise
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.03.2013; The Company of Biologists Limited; The Company of Biologists
• Subjects: Amidines - chemistry; Amidines - pharmacology; Amidines - therapeutic use; Animals; Apoptosis; Binding sites; Brain; Brain - enzymology; Brain - pathology; CD3 Complex - metabolism; Citrulline - metabolism; Demyelinating Diseases - enzymology; Demyelinating Diseases - pathology; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - enzymology; Encephalomyelitis, Autoimmune, Experimental - pathology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymes; Humans; Hydrolases - antagonists & inhibitors; Hydrolases - metabolism; Lymphocytes - drug effects; Lymphocytes - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - enzymology; Multiple Sclerosis - pathology; Optic Nerve - drug effects; Optic Nerve - pathology; Optic Nerve - ultrastructure; Pathogenesis; Peptides; Protein expression; Protein-Arginine Deiminases; Proteins; Spleen - drug effects; Spleen - metabolism; Spleen - pathology; Survival Analysis
• DOI: 10.1242/dmm.010520
• ISSN: 1754-8403

Multiple sclerosis (MS) is the most common CNS-demyelinating disease of humans, showing clinical and pathological heterogeneity and a general resistance to therapy. We first discovered that abnormal myelin hypercitrullination, even in normal-appearing white matter, by peptidylarginine deiminases (PADs) correlates strongly with disease severity and might have an important role in MS progression. Hypercitrullination is known to promote focal demyelination through reduced myelin compaction. Here we report that 2-chloroacetamidine (2CA), a small-molecule, PAD active-site inhibitor, dramatically attenuates disease at any stage in independent neurodegenerative as well as autoimmune MS mouse models. 2CA reduced PAD activity and protein citrullination to pre-disease status. In the autoimmune models, disease induction uniformly induced spontaneous hypercitrullination with citrulline+ epitopes targeted frequently. 2CA rapidly suppressed T cell autoreactivity, clearing brain and spinal cord infiltrates, through selective removal of newly activated T cells. 2CA essentially prevented disease when administered before disease onset or before autoimmune induction, making hypercitrullination, and specifically PAD enzymes, a therapeutic target in MS models and thus possibly in MS.