title: Activation of NOD2 in vivo induces IL-1beta production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling.
abstract: Nucleotide-binding and oligomerization domain 2 (NOD2) belongs to the emerging Nod-like receptor (NLR) family considered important in innate immunity. Mutations in NOD2 cause Blau syndrome, an inherited inflammation of eye, joints, and skin. Mutations in a homologous region of another NLR member, NALP3, cause autoinflammation, wherein IL-1beta plays a critical role. Here, we tested the hypothesis that IL-1beta is a downstream mediator of NOD2-dependent ocular inflammation. We used a mouse model of NOD2-dependent ocular inflammation induced by muramyl dipeptide (MDP), the minimal bacterial motif sensed by NOD2. We report that MDP-induced ocular inflammation generates IL-1beta and IL-18 within the eye in a NOD2- and caspase-1-dependent manner. Surprisingly, two critical measures of ocular inflammation, leukocyte rolling and leukocyte intravascular adherence, appear to be completely independent of IL-1 signaling effects, as caspase-1 and IL-1R1-deficient mice still developed ocular inflammation in response to MDP. In contrast to the eye, a diminished neutrophil response was observed in an in vivo model of MDP-induced peritonitis in caspase-1-deficient mice, suggesting that IL-1beta is not essential in NOD2-dependent ocular inflammation, but it is involved, in part, in systemic inflammation triggered by NOD2 activation. This disparity may be influenced by IL-1R antagonist (IL-1Ra), as we observed differential IL-1Ra levels in the eye versus plasma at baseline levels and in response to MDP treatment. This report reveals a new in vivo function of NOD2 within the eye yet importantly, distinguishes NOD2-dependent from NALP3-dependent inflammation, as ocular inflammation in mice occurred independently of IL-1beta.
authors.affiliation: Department of Ophthalmology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Stop: L467 IM, Portland, OR 97239, USA. rosenzwh@ohsu.edu
authors.forename: H L
authors.initials: HL
authors.lastname: Rosenzweig
authors.forename: T M
authors.initials: TM
authors.lastname: Martin
authors.forename: S R
authors.initials: SR
authors.lastname: Planck
authors.forename: K
authors.initials: K
authors.lastname: Galster
authors.forename: M M
authors.initials: MM
authors.lastname: Jann
authors.forename: M P
authors.initials: MP
authors.lastname: Davey
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: J T
authors.initials: JT
authors.lastname: Rosenbaum
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005123:Eye / Q000201:enzymology / Q000503:physiopathology*; D005128:Eye Diseases / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020170:Caspase 1