Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus

• Published in: The Journal of immunology (1950) 2012-04, Vol.188 (8), p.4113-4121
• Main Authors: Xu, Yuan, Lee, Pui Y, Li, Yi, Liu, Chao, Zhuang, Haoyang, Han, Shuhong, Nacionales, Dina C, Weinstein, Jason, Mathews, Clayton E, Moldawer, Lyle L, Li, Shi-Wu, Satoh, Minoru, Yang, Li-Jun, Reeves, Westley H
• Format: Article
• Language: English
• Subjects: Animals; Autoantibodies - biosynthesis; Autoantibodies - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Carcinogens; Cell Differentiation - immunology; Cell Movement - immunology; Cytokines - biosynthesis; Cytokines - immunology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Disease Models, Animal; Humans; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - immunology; Lupus Erythematosus, Systemic - chemically induced; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Terpenes; Th1-Th2 Balance
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103113

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.