title: IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus.
abstract: Interferon Regulatory Factors (IRFs) play fundamental roles in dendritic cell (DC) differentiation and function. In particular, IRFs are critical transducers of TLR signaling and dysregulation in this family of factors is associated with the development of autoimmune disorders such as Systemic Lupus Erythematosus (SLE). While several IRFs are expressed in DCs their relative contribution to the aberrant phenotypic and functional characteristics that DCs acquire in autoimmune disease has not been fully delineated. Mice deficient in both DEF6 and SWAP-70 (= Double-knock-out or DKO mice), two members of a unique family of molecules that restrain IRF4 function, spontaneously develop a lupus-like disease. Although autoimmunity in DKO mice is accompanied by dysregulated IRF4 activity in both T and B cells, SWAP-70 is also known to regulate multiple aspects of DC biology leading us to directly evaluate DC development and function in these mice. By monitoring Blimp1 expression and IL-10 competency in DKO mice we demonstrate that DCs in these mice exhibit dysregulated IL-10 production, which is accompanied by aberrant Blimp1 expression in the spleen but not in the peripheral lymph nodes. We furthermore show that DCs from these mice are hyper-responsive to multiple TLR ligands and that IRF4 plays a differential role in in these responses by being required for the TLR4-mediated but not the TLR9-mediated upregulation of IL-10 expression. Thus, DC dysfunction in lupus-prone mice relies on both IRF4-dependent and IRF4-independent pathways.
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, United States of America.
authors.forename: Michela
authors.initials: M
authors.lastname: Manni
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.
authors.forename: Briana G
authors.initials: BG
authors.lastname: Nixon
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.affiliation: Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, United States of America.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.|Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America.
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D016753:Interleukin-10; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D051193:Toll-Like Receptors; D000099218:Interferon Regulatory Factor-4; C473249:Def6 protein, mouse; C113365:Swap70 protein, mouse