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.

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

“…The increase in IL-17 pathway activation in feet of CHIKVinfected CCR2 Ϫ/Ϫ mice did not appear to be due to increased levels of Th17 cells (as was reported previously for collagen-induced arthritis [17]). Recently, immune complexes present during acute arthritis were shown to induce IL-17 production by neutrophils (65).…”

“…Ϫ/Ϫ mice is more severe, with increased macrophage and neutrophil infiltrates (16,17), whereas in other arthritis models, inhibition of CCL2 ameliorated disease (18,19). CCR2 deficiency was associated with reduced monocyte/macrophage infiltration in some settings (20)(21)(22) but not in others (16,23).…”

Mutant huntingtin impairs immune cell migration in Huntington disease

“…Consistent with this hypothesis, myeloid cells in mice mutant for the chemokine receptor Cx3cr1 are impaired in migration, leading to increased IL-1β levels and decreased synaptic plasticity (55,59). In mice with deletion of Ccr2, whose monocytes and macrophages also do not migrate properly, serum levels of IL-6 and IL-1β are elevated (33,60). Mice mutant for these chemokine receptors are also unable to clear infections, have impaired wound healing, and are unable to mount effective adaptive immune responses (33,(61)(62)(63).…”

Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection Through Bystander Activation Requiring IL-6

“…; 2 mg on day À1; 1 mg on day þ7) (21), or anti-IL-17A (BZN035, i.p. ; 0.5 mg on days À1, þ2, þ5 and twice weekly thereafter) (22) or with depleting doses of anti-NK1.1 (PK136, i.p. ; 0.5 mg on day À1 and 0.25 mg on days þ2 and þ4), with rapamycin (5 mg/kg/day on days À1, 0 and þ2) (Alexis Biochemicals, San Diego, CA) with anti-lymphocyte function-associated antigen 1 (LFA-1) (M17/4, i.p.…”