title: Complement component C5a permits the coexistence of pathogenic Th17 cells and type I IFN in lupus.
abstract: Systemic lupus erythematosus (SLE) is a type I IFN (IFN-I)-driven autoimmune disorder with exaggerated B and Th cell responses. Th17 cells, a recently identified Th cell subset, have been strongly implicated in the pathogenesis of SLE. Because IFN-I suppresses the generation and expansion of Th17 cells in an IL-27-dependent manner, it is unclear how pathogenic Th17 cells are generated in SLE in the presence of an environment characterized by high IFN-I levels. In this study, we showed that activation of c5aR on murine macrophages blocked IFN-I-mediated IL-27 production, thus permitting the development of Th17 cells. C5aR activation on IFN-I-responsive macrophages inhibits IRF-1-mediated transactivation of IL-27 gene expression via the PI3K/Akt pathway. Consistently, C5aR-deficient mice exhibited increased IL-27 expression and fewer Th17 cells and consequently developed reduced lupus nephritis in comparison with wild-type mice. In support of these findings in mice, we found that C5a inhibited IFN-I-induced IL-27 production from macrophages of lupus subjects. Moreover, the level of serum C5a correlated with Th17 frequency in peripheral blood. Collectively, these data indicate an essential role for C5a in the generation of pathogenic Th17 responses in SLE. Thus, therapeutic strategies to block C5aR activation may be beneficial for controlling pathogenic Th17-mediated inflammation in SLE.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Sudesh
authors.initials: S
authors.lastname: Pawaria
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Kritika
authors.initials: K
authors.lastname: Ramani
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Kelly
authors.initials: K
authors.lastname: Maers
authors.affiliation: Division of Pathology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Lawrence P
authors.identifier: http://orcid.org/0000-0001-5198-516X
authors.initials: LP
authors.lastname: Kane
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Marc C
authors.initials: MC
authors.lastname: Levesque
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; psb13@pitt.edu.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Biswas
mesh_terms: D000818:Animals; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology*
chemical_list: C000591759:C5ar1 protein, mouse; C486767:Il27 protein, mouse; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D007378:Interleukins; C494258:Irf1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a