title: Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis.
abstract: The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2-/- mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.
authors.affiliation: South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Texas, USA.
authors.forename: Marlon P
authors.initials: MP
authors.lastname: Quinones
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Ahuja
authors.forename: Fabio
authors.initials: F
authors.lastname: Jimenez
authors.forename: Jason
authors.initials: J
authors.lastname: Schaefer
authors.forename: Edgar
authors.initials: E
authors.lastname: Garavito
authors.forename: Arun
authors.initials: A
authors.lastname: Rao
authors.forename: George
authors.initials: G
authors.lastname: Chenaux
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology; D006801:Humans; D051379:Mice; D023421:Models, Animal; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D024043:Collagen Type II; D054390:Receptors, CCR2; D019707:Receptors, Chemokine