title: Spontaneous development of autoimmune uveitis Is CCR2 dependent.
abstract: Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow-derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4(+) T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity.
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California.
authors.forename: YuTing Feeling
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California.
authors.forename: Delu
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Diabetes Center, University of California, San Francisco, California.
authors.forename: Todd
authors.initials: T
authors.lastname: Metzger
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California.
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, California.
authors.forename: Marion
authors.initials: M
authors.lastname: Jeanne
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, California.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.affiliation: Diabetes Center, University of California, San Francisco, California.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California; Department of Ophthalmology, University of California, San Francisco, California; Department of Anatomy, University of California, San Francisco, California; School of Optometry, University of California, Berkeley, California; Vision Science Program, University of California, Berkeley, California. Electronic address: nancy.mcnamara@ucsf.edu.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology*; D012160:Retina / Q000276:immunology* / Q000473:pathology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2
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