Journal of Leukocyte Biology
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Published online before print September 17, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607402

Received for publication June 14, 2007.
Revised August 15, 2007.
Accepted for publication August 17, 2007.

Article

NLR proteins: integral members of innate immunity and mediators of inflammatory diseases

Jeanette M. Wilmanski *{dagger}{ddagger}, Tanja Petnicki-Ocwieja *{dagger}, and Koichi S. Kobayashi *{dagger}@

*Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; {dagger}Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA; and {ddagger}Department of Biology, Saint Peter’s College, Jersey City, New Jersey, USA

@ To whom correspondence should be addressed. E-mail: Koichi_Kobayashi{at}dfci.harvard.edu.


  Abstract

The innate immune system is the first line of defense against microorganisms and is conserved in plants and animals. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein family is a recent addition to the members of innate immunity effector molecules. These proteins are characterized by a central oligomerization domain, termed neuronal apoptosis inhibitory protein (NAIP)/MHC class II transcription activator/incompatibility locus protein from Podospora anserina/telomerase-associated protein (NACHT; or nucleotide-binding domain/NOD), and a protein interaction domain, leucine-rich repeats (LRRs) at the C terminus. It has been shown that NLR proteins are localized to the cytoplasm and recognize microbial products. To date, it is known that Nod1 and Nod2 detect bacterial cell wall components, whereas intercostal-to-pulmonary arterial fistula and NAIP detect bacterial flagellin, and NACHT/LRR/Pyrin 1 has been shown to detect anthrax lethal toxin. NLR proteins comprise a diverse protein family (over 20 in humans), indicating that NLRs have evolved to acquire specificity to various pathogenic microorganisms, thereby controlling host-pathogen interactions. Activation of NLR proteins results in inflammatory responses mediated by NF-{kappa}B, MAPK, or Caspase-1 activation, accompanied by subsequent secretion of proinflammatory cytokines. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interaction and inflammatory responses. Therefore, understanding NLR signaling is important for the therapeutic intervention of various infectious and inflammatory diseases.

Key Words: NACHT • host-pathogen interaction • Nod2 • Crohn’s disease






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