NOD2, the gene responsible for familial granulomatous uveitis, in a mouse model of uveitis.
OBJECTIVE
NOD2 plays an important role in the recognition of intracellular bacteria through its ability to sense the components of bacterial peptidoglycan (PGN), namely muramyl dipeptide (MDP) and muramyl tripeptide (MTP). Specific mutations in the human NOD2 gene cause Blau syndrome, an autosomal dominant form of uveitis, arthritis, and dermatitis. As a first step toward understanding the role of NOD2 in the pathogenesis of uveitis, the authors developed a mouse model of MDP-dependent uveitis.


METHODS
BALB/c mice and mice deficient in L-selectin or NOD2 received intravitreal injection of MDP, MTP, or PGN. The intravascular response within the iris and cellular infiltration was quantified by intravital microscopy and histologic assessment.


RESULTS
MDP induced an acute, ocular inflammatory response, wherein rolling and adhering leukocytes within the vasculature were significantly increased within 6 hours after MDP treatment. A minor increase in cellular infiltration occurred at 12 hours after MDP treatment. The adhesion molecule L-selectin participated in MDP-induced vascular inflammation because L-selectin knockout mice showed a significant decrease in the number of rolling cells. Importantly, NOD2 plays an essential role in ocular inflammation induced by MDP, as indicated by the fact that uveitis did not develop in Nod2 knockout mice in response to MDP. Nod2 knockout mice also showed abolished ocular inflammation in response to MTP but not to PGN treatment.


CONCLUSIONS
These findings demonstrate a novel mouse model of uveitis, wherein NOD2 plays an essential role in inflammation induced by the minimal components of PGN. Thus, innate immune responses mediated by NOD2 may participate in the development of uveitis in response to bacterial products.
Rosenzweig
Holly L
HL
Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA. rosenzwh@ohsu.edu
Martin
Tammy M
TM
Jann
Monica M
MM
Planck
Stephen R
SR
Davey
Michael P
MP
Kobayashi
Koichi
K
Flavell
Richard A
RA
Rosenbaum
James T
JT
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006099:Granuloma / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D007498:Iris / Q000098:blood supply; D019041:L-Selectin / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D014605:Uveitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology
D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D019041:L-Selectin; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C035104:muramylNAc-Ala-isoGln-Lys-tripeptide