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

PLoS One. 2011;6(10):e25833. doi: 10.1371/journal.pone.0025833. Epub 2011 Oct 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antibodies / therapeutic use
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Autoantibodies / immunology
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Bone Marrow / drug effects
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • Cell Proliferation / drug effects
  • Epitopes / immunology
  • Immunization
  • Interleukin-17 / immunology
  • Joints / immunology
  • Joints / pathology
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Monocytes / drug effects
  • Monocytes / immunology
  • Neutrophil Infiltration / drug effects
  • Neutrophil Infiltration / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Receptors, CCR2 / blood
  • Receptors, CCR2 / deficiency*
  • Th17 Cells / cytology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology*
  • Up-Regulation / drug effects
  • Up-Regulation / immunology

Substances

  • Antibodies
  • Autoantibodies
  • Ccr2 protein, mouse
  • Epitopes
  • Interleukin-17
  • Receptors, CCR2