Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis.
In addition to its role in innate immunity, nucleotide oligomerization domain 2 (NOD2) has been shown to play a suppressive role in models of colitis. Notably, mutations in NOD2 cause the inherited granulomatous disease of the joints called Blau syndrome, thereby linking NOD2 with joint disease as well. However, the role of NOD2 in joint inflammation has not been clarified. We demonstrate here that NOD2 is functional within the mouse joint and promotes inflammation, as locally or systemically administered muramyl dipeptide (MDP; the NOD2 agonist) resulted in significant joint inflammation that was abolished in NOD2-deficient mice. We then sought to investigate the role of NOD2 in a mouse model of inflammatory arthritis dependent on adaptive immunity using TCR-transgenic mice whose T cells recognized the dominant epitope of proteoglycan (PG). Mice immunized with PG in the presence of MDP developed a more severe inflammatory arthritis and histopathology within the joints. Antigen-specific activation of splenocytes was enhanced by MDP with respect to IFN-gamma production, which would be consistent with the Th1-mediated disease in vivo. Intriguingly, NOD2 deficiency did not alter the PG-induced arthritis, indicating that NOD2 does not play an essential role in this model of joint disease when it is not activated by MDP. In conclusion, we demonstrate that in a model of inflammatory arthritis dependent on T and B cell priming, NOD2 activation potentiates disease. However, the absence of NOD2 does not alter the course of inflammatory arthritis, in contrast to models of intestinal inflammation.
Rosenzweig
H L
HL
Casey Eye Institute, Oregon Health and Science University, Portland, OR 97219, USA. rosenzwh@ohsu.edu
Jann
M M
MM
Glant
T T
TT
Martin
T M
TM
Planck
S R
SR
van Eden
W
W
van Kooten
P J S
PJ
Flavell
R A
RA
Kobayashi
K S
KS
Rosenbaum
J T
JT
Davey
M P
MP
D000818:Animals; D017951:Antigen Presentation; D001168:Arthritis / Q000139:chemically induced / Q000209:etiology*; D001402:B-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D011509:Proteoglycans / Q000009:adverse effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D053473:Nod2 Signaling Adaptor Protein; D011509:Proteoglycans