Microreview Intracellular NOD-like receptors in innate immunity, infection and disease Luigi Franchi, Jong-Hwan Park, Michael H. Shaw, Noemi Marina-Garcia, Grace Chen, Yun-Gi Kim and Gabriel Núñez* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Summary The innate immune system comprises several classes of pattern-recognition receptors, including Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain-like receptors (NLRs). TLRs recognize microbes on the cell surface and in endo- somes, whereas NLRs sense microbial molecules in the cytosol. In this review, we focus on the role of NLRs in host defence against bacterial pathogens. Nod1 and Nod2 sense the cytosolic presence of mol- ecules containing meso-diaminopimelic acid and muramyl dipeptide respectively, and drive the activa- tion of mitogen-activated protein kinase and NF-kB. In contrast, Ipaf, Nalp1b and Cryopyrin/Nalp3 promote the assembly of inflammasomes that are required for the activation of caspase-1. Mutation in several NLR members, including NOD2 and Cryopyrin, is associ- ated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defence and the pathogenesis of inflammatory diseases. Introduction Upon encountering pathogenic microorganisms, the immunocompetent host activates two distinct effector mechanisms, the innate and the adaptive immune defences, to ensure effective elimination of the invading microbe. Unlike adaptive immune responses, the innate immune system relies on phagocytic and non- haematopietic cells to sense the presence of pathogens. The initial recognition of microbes is mediated by a set of germline-encoded pattern-recognition receptors (PRRs) that sense highly conserved microbial motifs, so-called pathogen-associated molecular patterns (PAMPs) (Kawai and Akira, 2006). PRRs can be found in the extracellular space, integrated in cellular membranes or in the cytosol. Among the membrane-bound PRRs, the best-known PRRs are the Toll-like receptors (TLRs) that sense a wide array of microbial ligands at the cell surface or within endosomes (Kawai and Akira, 2006). Cytoplasmic PRRs include the caspase-recruiting domain (CARD) helicases, such as retinoic acid-inducible protein I and melanoma- differentiation-associated protein 5, which are involved in antiviral responses (Kawai and Akira, 2006), and the nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family that recognize primarily microbial molecules of bacterial origin (Inohara et al., 2005). In humans, the NLR family is composed of 23 cytosolic proteins characterized by the presence of a conserved NOD domain and leucine-rich repeats (LRRs) (Inohara et al., 2005). The general domain structure of the NLR family members includes an amino-terminal effector region that consists of a protein–protein interaction domain such as the CARD, Pyrin or BIR domain, a cen- trally located NOD domain, and carboxyl-terminal LRRs that are involved in microbial sensing (Inohara et al., 2005). Some members of the NLR family, namely Nod1 and Nod2, mediate activation of NF-kB and mitogen- activated protein kinases (MAPKs) in response to peptidoglycan-related molecules (McDonald et al., 2005). A different set of NLRs, including Nalp1, Cryopyrin/Nalp3 and Ipaf, are involved in the activation of the protease caspase-1 (Franchi et al., 2006a). Ipaf is activated by bacterial flagellin (Franchi et al., 2006b; Miao et al., 2006); mouse Nalp1b by lethal toxin produced by Bacillus anthracis (Boyden and Dietrich, 2006); Cryopyrin is acti- vated in response to a variety of microbial molecules (Kanneganti et al., 2006; 2007; Mariathasan et al., 2006; Sutterwala et al., 2006) as well as endogenous ligands, such as uric acid crystals (Martinon et al., 2006). While certain microbial molecules, such as meso- diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP) (McDonald et al., 2005), are exclusively recog- nized by NLRs, other PAMPs are also sensed by TLR Received 1 August, 2007; revised 6 September, 2007; accepted 13 September, 2007. *For correspondence. E-mail bclx@umich.edu; Tel. (+1) 734 764 8514; Fax (+1) 734 647 9654. Cellular Microbiology (2008) 10(1), 1–8 doi:10.1111/j.1462-5822.2007.01059.x First published online 18 October 2007 © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd