TY - JOUR
T1 - Activation of NOD2 in vivo induces IL-1β production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling
AU - Rosenzweig, H. L.
AU - Martin, T. M.
AU - Planck, S. R.
AU - Galster, K.
AU - Jann, M. M.
AU - Davey, M. P.
AU - Kobayashi, K.
AU - Flavell, R. A.
AU - Rosenbaum, J. T.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - 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-1β plays a critical role. Here, we tested the hypothesis that IL-1β 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-1β 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-1β 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-1β.
AB - 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-1β plays a critical role. Here, we tested the hypothesis that IL-1β 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-1β 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-1β 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-1β.
KW - Cytokines
KW - Transgenic/knockout mice
UR - http://www.scopus.com/inward/record.url?scp=48649100466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48649100466&partnerID=8YFLogxK
U2 - 10.1189/jlb.0108015
DO - 10.1189/jlb.0108015
M3 - Article
C2 - 18495787
AN - SCOPUS:48649100466
SN - 0741-5400
VL - 84
SP - 529
EP - 536
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 2
ER -