title: Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus.
abstract: Genetic polymorphisms of IFN regulatory factor 5 (IRF5) are associated with an increased risk of lupus in humans. In this study, we examined the role of IRF5 in the pathogenesis of pristane-induced lupus in mice. The pathological response to pristane in IRF5(-/-) mice shared many features with type I IFN receptor (IFNAR)(-/-) and TLR7(-/-) mice: production of anti-Sm/RNP autoantibodies, glomerulonephritis, generation of Ly6C(hi) monocytes, and IFN-I production all were greatly attenuated. Lymphocyte activation following pristane injection was greatly diminished in IRF5(-/-) mice, and Th cell differentiation was deviated from Th1 in wild-type mice toward Th2 in IRF5(-/-) mice. Th cell development was skewed similarly in TLR7(-/-) or IFNAR(-/-) mice, suggesting that IRF5 alters T cell activation and differentiation by affecting cytokine production. Indeed, production of IFN-I, IL-12, and IL-23 in response to pristane was markedly decreased, whereas IL-4 increased. Unexpectedly, plasmacytoid dendritic cells (pDC) were not recruited to the site of inflammation in IRF5(-/-) or MyD88(-/-) mice, but were recruited normally in IFNAR(-/-) and TLR7(-/-) mice. In striking contrast to wild-type mice, pristane did not stimulate local expression of CCL19 and CCL21 in IRF5(-/-) mice, suggesting that IRF5 regulates chemokine-mediated pDC migration independently of its effects on IFN-I. Collectively, these data indicate that altered production of IFN-I and other cytokines in IRF5(-/-) mice prevents pristane from inducing lupus pathology by broadly affecting T and B lymphocyte activation/differentiation. Additionally, we uncovered a new, IFN-I-independent role of IRF5 in regulating chemokines involved in the homing of pDCs and certain lymphocyte subsets.
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610-0221, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pui Y
authors.initials: PY
authors.lastname: Lee
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Haoyang
authors.initials: H
authors.lastname: Zhuang
authors.forename: Shuhong
authors.initials: S
authors.lastname: Han
authors.forename: Dina C
authors.initials: DC
authors.lastname: Nacionales
authors.forename: Jason
authors.initials: J
authors.lastname: Weinstein
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Shi-Wu
authors.initials: SW
authors.lastname: Li
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013729:Terpenes; D058408:Th1-Th2 Balance
chemical_list: D001323:Autoantibodies; D002273:Carcinogens; D016207:Cytokines; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D013729:Terpenes; C009042:pristane