Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis

• Published in: PloS one Vol. 6; no. 10; p. e25833
• Main Authors: Rampersad, Rishi R, Tarrant, Teresa K, Vallanat, Christopher T, Quintero-Matthews, Tatiana, Weeks, Michael F, Esserman, Denise A, Clark, Jennifer, Di Padova, Franco, Patel, Dhavalkumar D, Fong, Alan M, Liu, Peng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.10.2011; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies; Antibodies - pharmacology; Antibodies - therapeutic use; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Autoantibodies - immunology; Autoimmune diseases; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmunity; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Bacterial infections; Biology; Biomedical research; Bone marrow; Bone Marrow - drug effects; Bone Marrow - immunology; Bone Marrow - pathology; CCR2 protein; Cell Proliferation - drug effects; Chemokines; Collagen; Collagen (type II); Cytokines; Dendritic cells; Disease; Drainage control; Emigration; Epitopes - immunology; Government agencies; Helper cells; Immune system; Immunization; Immunologic factors; Immunoregulation; Inflammation; Inflammatory diseases; Interleukin 17; Interleukin 6; Interleukin-17 - immunology; Joint diseases; Joints - immunology; Joints - pathology; Ligands; Lymph nodes; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Monocyte chemoattractant protein 1; Monocytes; Monocytes - drug effects; Monocytes - immunology; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - immunology; Neutrophils - drug effects; Neutrophils - immunology; Pathogenesis; Proteins; Receptors, CCR2 - blood; Receptors, CCR2 - deficiency; Rheumatoid arthritis; Risk factors; Rodents; Spleen; T cell receptors; T cells; Th17 Cells - cytology; Th17 Cells - drug effects; Th17 Cells - immunology; Tumor necrosis factor-TNF; Up-Regulation - drug effects; Up-Regulation - immunology; North Carolina; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025833

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.