Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: dependence on IFN-gamma.
OBJECTIVE
Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-gamma, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis.


METHODS
Mice deficient in IFN-gamma, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-gamma. IFN-gamma production in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy.


RESULTS
NOD2 activation resulted in the production of IFN-gamma within the eye. Deficiency in IFN-gamma diminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-gamma markedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-gamma to enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-gamma and MDP cotreatment on adhering and infiltrating cells.


CONCLUSIONS
IFN-gamma was identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-gamma in vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-gamma may occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.
Rosenzweig
Holly L
HL
Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239, USA. rosenzwh@ohsu.edu
Kawaguchi
Tatsushi
T
Martin
Tammy M
TM
Planck
Stephen R
SR
Davey
Michael P
MP
Rosenbaum
James T
JT
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000633:toxicity; D000276:Adjuvants, Immunologic; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D007499:Iris Diseases / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology
D000276:Adjuvants, Immunologic; D039481:CD11b Antigen; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma