title: Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis.
abstract: CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2(-/-) mice compared to WT controls (p = 0.017), whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2-6-fold elevated in the serum and 22-28-fold increased in the arthritic joints in CCR2(-/-) mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints). Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2(-/-) mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2(-/-) mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2(-/-) mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.
authors: Department of Medicine, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors: Rishi R
authors: RR
authors: Rampersad
authors: Teresa K
authors: TK
authors: Tarrant
authors: Christopher T
authors: CT
authors: Vallanat
authors: Tatiana
authors: T
authors: Quintero-Matthews
authors: Michael F
authors: MF
authors: Weeks
authors: Denise A
authors: DA
authors: Esserman
authors: Jennifer
authors: J
authors: Clark
authors: Franco
authors: F
authors: Di Padova
authors: Dhavalkumar D
authors: DD
authors: Patel
authors: Alan M
authors: AM
authors: Fong
authors: Peng
authors: P
authors: Liu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D007114:Immunization; D020381:Interleukin-17 / Q000276:immunology; D007596:Joints / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D054390:Receptors, CCR2 / Q000097:blood / Q000172:deficiency*; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D001323:Autoantibodies; C515335:Ccr2 protein, mouse; D000939:Epitopes; D020381:Interleukin-17; D054390:Receptors, CCR2