Nod Like Receptors

Annu. Rev. Pathol. Mech. Dis. 2009.4:365-398


NOD-Like Receptors: Role in Innate Immunity and Inflammatory Disease
Grace Chen, Michael H. Shaw, Yun-Gi Kim, ˜ and Gabriel Nunez
Departments of Pathology and Internal Medicine and the Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109; email: gchenry@umich.edu; mhshaw@umich.edu; yungikim@umich.edu;bclx@umich.edu

Annu. Rev. Pathol. Mech. Dis. 2009. 4:365–98 First published online as a Review in Advance on October 17, 2008 The Annual Review of Pathology: Mechanisms of Disease is online at pathmechdis.annualreviews.org This article’s doi: 10.1146/annurev.pathol.4.110807.092239 Copyright c 2009 by Annual Reviews. All rights reserved 1553-4006/09/0228-0365$20.00

Key Words
caspase-1, Crohn’sdisease, IL-1, NOD2, NLRP3

Abstract
The NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. Since the discovery of the first NLR almost 10 years ago, the study of this special class of microbial sensors has burgeoned; consequently, a better understanding of the mechanism by which these receptors recognizemicrobes and other danger signals and of how they activate inflammatory signaling pathways has emerged. Moreover, in addition to their primary role in host defense against invading pathogens, their ability to regulate nuclear factor–kappa B (NF-κB) signaling, interleukin-1-beta (IL-1β) production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory humandiseases.

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INTRODUCTION
PAMPs: pathogenassociated molecular patterns PRRs: pathogen recognition receptors LPS: lipopolysaccharide PGN: peptidoglycan TLRs: Toll-like receptors

Essential to human survival is the ability to eradicate pathogenic microorganisms. To ensure the efficient detection and removal of harmful microbes, two effector mechanisms have evolved: the innate and adaptiveimmune systems. The adaptive immune response is characterized by a delayed response involving gene rearrangements for the clonal selection and expansion of T cell and B cell lymphocytes with antigen-specific receptors. This process results in the generation of a diverse, yet specific repertoire of immune effectors that also contribute to immunologic memory. The innate immune system, however, israpidly activated and does not require the somatic gene rearrangements that form the cornerstone of adaptive immunity. It represents one of the first lines of defense against microorganisms, whereby conserved microbial structures known as pathogen-associated molecular patterns (PAMPs) are recognized by germlineencoded innate immune receptors, also known as pathogen recognition receptors (PRRs). Examplesof PAMPs include lipopolysaccharides (LPS), peptidoglycan (PGN), flagellin, and microbial nucleic acids. Recognition of these PAMPs by PRRs results in the activation of signaling pathways, which promotes an inflammatory, antimicrobial response. Emerging data have also demonstrated a link between the innate PRRs and the activation of the adaptive immune response that can act in concert in defenseagainst invasive organisms (1). Moreover, it has also become apparent that these receptors are involved in sensing not only invading pathogens, but also endogenous nonmicrobial “danger” or stress signals, both of which result in the activation of inflammatory signaling pathways such as nuclear factor–kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). This upstream link to complex effectorpathways highlights the importance of these immune receptors in both microbial defense and the pathogenesis of noninfectious, inflammatory diseases when signaling becomes dysregulated.

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Three major classes of PRRs have been identified: (a) the Toll-like receptors...