NOD2 and Uveitis

Summary

Principal Investigator: HOLLY LALLMAN ROSENZWEIG
Affiliation: Oregon Health and Science University
Country: USA
Abstract: DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT. The underlying mechanisms of uveitis, or intraocular inflammation, remain poorly understood. However, a recently identified gene called NOD2 provides important insight into the genetics involved in the pathogenesis of uveitis. Specific mutations within NOD2 are the cause of an inherited multisystem granulomatous disease affecting the eye, joints and skin that develop in the absence of infection. While pathogenic mutations have been identified, the functions of NOD2 responsible for initiation of ocular inflammation have not. We have succeeded in establishing a model of NOD2-dependent uveitis, wherein NOD2 is activated by its synthetic agonist muramyl dipeptide (MDP). We propose to use this model to investigate the mechanisms by which NOD2 could initiate uveitis either via its direct activation by its agonist (in the absence of infection as might occur in Blau syndrome) or by its ability to regulate inflammation induced by either toll-like receptors (TLRs) or by the homologous family member, NOD1. Specifically, we will 1) Identify which cells respond to MDP and investigate the role of IFNg as a modulator of NOD2-driven ocular inflammation;2) Since our discovery that NOD1 triggers uveitis, we propose to investigate whether NOD1 and NOD2-induced ocular inflammatory response are distinguishable and whether cross-talk occurs;and 3) Since NOD2 appears to exert its most measurable biological effects when it modulates TLRs, we will explore the capacity of NOD2 to regulate TLR responses within the eye. This aim will also explore how MDP affects the inflammatory response triggered by IL-1b. Together, these studies will have considerable implications for understanding pathological mechanisms involved in uveitis. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE/SIGNIFICANCE. "Experiments" in nature can lead to personal suffering while concomitantly offering unique opportunities to elucidate human biology. This is best exemplified in Blau syndrome, wherein a single base pair change in the NOD2 gene results in complete penetrance for the induction of uveitis and multisystem granulomatous disease. The connection between a single gene and uveitis offers enormous potential to study the pathogenesis of uveitis.
Funding Period: 2009-08-01 - 2013-07-31
more information: NIH RePORT

Top Publications

  1. pmc 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
    H L Rosenzweig
    Department of Ophthalmology, Oregon Health and Science University, 3181 S W Sam Jackson Park Rd, Mail Stop L467 IM, Portland, OR 97239, USA
    J Leukoc Biol 84:529-36. 2008
  2. pmc Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis
    Jelena M Kezic
    Casey Eye Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    Arthritis Res Ther 14:R18. 2012
  3. pmc Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis
    Jenna S Clowers
    VA Medical Center, Portland, Oregon 97239, USA
    Br J Ophthalmol 97:504-10. 2013
  4. pmc Nucleotide-binding oligomerization domain 2 and Toll-like receptor 2 function independently in a murine model of arthritis triggered by intraarticular peptidoglycan
    Holly L Rosenzweig
    Oregon Health and Science University, Portland, OR 97239, USA
    Arthritis Rheum 62:1051-9. 2010
  5. pmc Dectin-1 and NOD2 mediate cathepsin activation in zymosan-induced arthritis in mice
    Holly L Rosenzweig
    Oregon Health and Science University, Mail stop L467 AD, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    Inflamm Res 60:705-14. 2011
  6. pmc Impact of IL-1 signalling on experimental uveitis and arthritis
    Stephen R Planck
    Casey Eye Institute, Oregon Health and Science University, Portland, OR 97239, USA
    Ann Rheum Dis 71:753-60. 2012
  7. pmc Interplay between innate and adaptive immunity in the development of non-infectious uveitis
    Francois Willermain
    Department of Ophthalmology, CHU St Pierre and Brugmann, Universite Libre de Bruxelles, Belgium
    Prog Retin Eye Res 31:182-94. 2012
  8. pmc The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
    Inflamm Res 61:225-31. 2012
  9. pmc NOD2 deficiency results in increased susceptibility to peptidoglycan-induced uveitis in mice
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA
    Invest Ophthalmol Vis Sci 52:4106-12. 2011
  10. pmc NLRs in immune privileged sites
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
    Curr Opin Pharmacol 11:423-8. 2011

Scientific Experts

  • HOLLY LALLMAN ROSENZWEIG
  • J T Rosenbaum
  • Jenna S Clowers
  • Stephen R Planck
  • Jordan J Allensworth
  • Francois Willermain
  • Jelena M Kezic
  • Ellen J Lee
  • April Woods
  • Martin J Nicklin
  • Tibor T Glant
  • Andrew D Dick
  • Travis Behrend
  • Bahram Bodaghi
  • Gerhild Wildner
  • Sarah Childers

Detail Information

Publications13

  1. pmc 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
    H L Rosenzweig
    Department of Ophthalmology, Oregon Health and Science University, 3181 S W Sam Jackson Park Rd, Mail Stop L467 IM, Portland, OR 97239, USA
    J Leukoc Biol 84:529-36. 2008
    ..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...
  2. pmc Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis
    Jelena M Kezic
    Casey Eye Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    Arthritis Res Ther 14:R18. 2012
    ....
  3. pmc Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis
    Jenna S Clowers
    VA Medical Center, Portland, Oregon 97239, USA
    Br J Ophthalmol 97:504-10. 2013
    ....
  4. pmc Nucleotide-binding oligomerization domain 2 and Toll-like receptor 2 function independently in a murine model of arthritis triggered by intraarticular peptidoglycan
    Holly L Rosenzweig
    Oregon Health and Science University, Portland, OR 97239, USA
    Arthritis Rheum 62:1051-9. 2010
    ..This study was undertaken to investigate NOD-2 function in an experimental model of arthritis and to explore the potential interplay between Toll-like receptor 2 (TLR-2) and NOD-2 in joint inflammation...
  5. pmc Dectin-1 and NOD2 mediate cathepsin activation in zymosan-induced arthritis in mice
    Holly L Rosenzweig
    Oregon Health and Science University, Mail stop L467 AD, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    Inflamm Res 60:705-14. 2011
    ..Activation of pattern recognition receptors (PRR) may contribute to arthritis. Here, we elucidated the role of NOD2, a genetic cause of inflammatory arthritis, and several other PRR in a murine model of inflammatory arthritis...
  6. pmc Impact of IL-1 signalling on experimental uveitis and arthritis
    Stephen R Planck
    Casey Eye Institute, Oregon Health and Science University, Portland, OR 97239, USA
    Ann Rheum Dis 71:753-60. 2012
    ....
  7. pmc Interplay between innate and adaptive immunity in the development of non-infectious uveitis
    Francois Willermain
    Department of Ophthalmology, CHU St Pierre and Brugmann, Universite Libre de Bruxelles, Belgium
    Prog Retin Eye Res 31:182-94. 2012
    ..Herein, we extrapolate from the basic mechanisms of activation and control of innate and adaptive immunity to how autoinflammatory and autoimmune pathways contribute to disease development in non-infectious uveitis patients...
  8. pmc The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
    Inflamm Res 61:225-31. 2012
    ....
  9. pmc NOD2 deficiency results in increased susceptibility to peptidoglycan-induced uveitis in mice
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA
    Invest Ophthalmol Vis Sci 52:4106-12. 2011
    ..Whether NOD2 exerts a similar capacity in the regulation of ocular inflammation to PGN has not been explored...
  10. pmc NLRs in immune privileged sites
    Holly L Rosenzweig
    Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
    Curr Opin Pharmacol 11:423-8. 2011
    ..Many NLRs are expressed within the brain and eye and in this review, we discuss their roles in the inflammation of the central nervous system (CNS) and uveitis...
  11. pmc Contrasting ocular effects of local versus systemic endotoxin
    James T Rosenbaum
    Casey Eye Institute, Portland, Oregon 97239, USA
    Invest Ophthalmol Vis Sci 52:6472-7. 2011
    ..The hypothesis that systemic LPS desensitizes leukocytes to the stimuli responsible for transmigration offers a plausible explanation for this discordance...
  12. pmc Investigation of the differential potentials of TLR agonists to elicit uveitis in mice
    Jordan J Allensworth
    Casey Eye Institute, Portland, Oregon, USA
    J Leukoc Biol 90:1159-66. 2011
    ..Our data demonstrate the eye's responsiveness to a diverse array of microbial products, which activates TLRs, and reveal differences in relative cellular response among the various TLR agonists in vivo...