NOD2 deficiency results in increased susceptibility to peptidoglycan-induced uveitis in mice.

Abstract

PURPOSE:

The innate immune receptor NOD2 is a genetic cause of uveitis (Blau syndrome). Intriguingly, in the intestine where polymorphisms of NOD2 predispose to Crohn's disease, NOD2 reportedly suppresses inflammation triggered by the bacterial cell wall component, peptidoglycan (PGN). Whether NOD2 exerts a similar capacity in the regulation of ocular inflammation to PGN has not been explored.

METHODS:

NOD2, NOD1, or MyD88 knockout (KO) mice and their wild-type (WT) controls were administered an intravitreal injection of PGN (a metabolite of which is the NOD2 agonist, muramyl dipeptide), or synthetic TLR2/1 and TLR2/6 agonists, Pam₃CSK4 and FSL-1. Ocular inflammation was assessed by intravital microscopy and histopathology. Cytokine production in eye tissue homogenates was measured by ELISA.

RESULTS:

PGN triggered uveitis in mice. This inflammation was abolished in the absence of the TLR signaling mediator MyD88. NOD2 exerted a negative regulatory role because PGN-triggered eye inflammation was exacerbated in NOD2 KO mice. Increased intravascular response coincided with enhanced leukocytes within the aqueous and vitreous humors. The enhanced susceptibility of NOD2 KO mice to PGN uveitis coincided with increased cytokine production of IL-12p40, IL-17, and IL-23 but not IL-12p70, TNFα, or IFNγ. NOD1 deficiency did not result in the same sensitivity to PGN. Ocular inflammation induced by synthetic TLR2 agonists required MyD88 but not NOD2 or NOD1.

CONCLUSIONS:

NOD2 may serve differential roles in the eye to promote inflammation while also tempering cell responses to PGN akin to what has been reported in colitis.

• Authors: Holly L Rosenzweig, Kellen Galster, Emily E Vance, Joe Ensign-Lewis, Gabriel Nunez, Michael P Davey, James T Rosenbaum
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 7 Pg. 4106-12 (Jun 09 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 21296813 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Nod1 Signaling Adaptor Protein
• Nod1 protein, mouse
• Nod2 Signaling Adaptor Protein
• Nod2 protein, mouse
• Peptidoglycan
• Tlr2 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptors

Topics

• Animals
• Aqueous Humor
• Cytokines (biosynthesis)
• Disease Susceptibility
• Eye (metabolism)
• Immunity, Innate
• Intravitreal Injections
• Leukocytes (pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Myeloid Differentiation Factor 88 (deficiency)
• Nod1 Signaling Adaptor Protein (metabolism)
• Nod2 Signaling Adaptor Protein (deficiency, metabolism)
• Peptidoglycan (administration & dosage)
• Signal Transduction
• Toll-Like Receptor 2 (agonists)
• Toll-Like Receptors (metabolism)
• Uveitis (chemically induced)
• Vitreous Body (pathology)