CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium.
The host factors that influence autoimmune arthritides such as rheumatoid arthritis have not been fully elucidated. We previously found that genetic inactivation of CC chemokine receptor 2 (CCR2) in the arthritis-prone DBA/1j mouse strain significantly increases the susceptibility of this strain to autoimmune arthritis induced by immunization with collagen type II (CII) and complete Freund's adjuvant (CFA). Here, we show that following intradermal infection with Mycobacterium avium, a similar arthritis phenotype was detected in Ccr2-null mice in the DBA/1j, but not in the BALB/c background. The failure to develop arthritis in Ccr2-null BALB/c mice occurred in the face of high bacterial burdens and low interferon gamma (IFNgamma) production. By contrast, Ccr2-null DBA/1j mice had low bacterial burdens, produced normal amounts of IFNgamma, and had high titers of autoantibodies against CII. Thus, the Ccr2-null state in an arthritic-prone genetic background leads to increased arthritis susceptibility following infectious (M. avium) and noninfectious (CII/CFA) challenges. Because CCR2 serves as a negative regulator of murine arthritis, caution might need to be exercised while testing CCR2 blockers in human arthritis or other diseases. These findings also indicate that Ccr2-null DBA/1j mice might serve as a valuable model system to uncover the immunological determinants of arthritis and to test novel antiarthritic agents.
Quinones
Marlon P
MP
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX, USA.
Jimenez
Fabio
F
Martinez
Hernan
H
Estrada
Carlos A
CA
Willmon
Opal
O
Dudley
Molly
M
Kuziel
William A
WA
Melby
Peter C
PC
Reddick
Robert L
RL
Ahuja
Sunil K
SK
Ahuja
Seema S
SS
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009162:Mycobacterium avium; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D014382:Tuberculosis, Cutaneous / Q000150:complications*
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D024043:Collagen Type II; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D007371:Interferon-gamma