Nucleotide-Binding Oligomerization Domain-Like
Receptors: Intracellular Pattern Recognition Molecules
for Pathogen Detection and Host Defense1
Luigi Franchi, Christine McDonald, Thirumala-Devi Kanneganti, Amal Amer, and
Gabriel Nu ´n ˜ez2
The nucleotide binding oligomerization domain-like re-
ceptor (NLR) family of pattern recognition molecules is
involved in a diverse array of processes required for host
immune responses against invading pathogens. Unlike
TLRs that mediate extracellular recognition of microbes,
several NLRs sense pathogens in the cytosol and upon ac-
TLRs and NLRs differ in their mode of pathogen recogni-
tion and function, they share similar domains for micro-
bial sensing and cooperate to elicit immune responses
against the pathogen. Genetic variation in several NLR
genes is associated with the development of inflammatory
Further understanding of NLRs should provide critical
genesis of inflammatory diseases. The Journal of Immu-
nology, 2006, 177: 3507–3513.
ence of infection is through pathogen recognition molecules
that detect the presence of unique microbial and viral compo-
nents called pathogen-associated molecular patterns (PAMPs)3
(i.e., LPS, lipoteichoic acid, and peptidoglycan), specialized
bacterial proteins (i.e., flagellin), as well as nucleic acid struc-
tures unique to bacteria and viruses (i.e., CpG DNA, dsRNA)
(2). Three main families of pathogen recognition molecules co-
operate in host defense and include TLRs, nucleotide-binding
oligomerization domain (Nod)-like receptors (NLRs), and ret-
inoid acid-inducible gene 1-like receptors (2). The detection of
PAMPs by TLRs, NLRs, and retinoid acid-inducible gene
n effective immune response against microbial infec-
tion requires both the ability to sense the presence of
the infectious agent, as well as the ability to destroy
1-like receptors stimulates the activation of proinflammatory
signaling pathways and caspases, as well as antiviral and bacte-
ricidal responses (2, 3). The coordination and cooperation of
responses triggered by these pathogen sensors tailor the im-
mune response to effectively abrogate the specific infection (2).
Genetic mutations that cause alterations in these signaling
pathways frequently result in inflammatory disease or immune
disorders (4). Recent advances have been made in our under-
standing of the role of NLRs and their cooperation with TLRs
in innate immunity and are the focus of this review.
NLR family of pathogen sensors
The NLR family (NLRs, also called Nod-leucine-rich repeats
(LRRs), NACHT-LRRs, or CATEPILLER proteins) is com-
conserved Nod (3). The general domain structure of these pro-
teins include an amino-terminal effector binding region that
consists of protein-protein interaction domains such as caspase
recruitment domains (CARD), pyrin, or baculovirus inhibitor
repeat domains, a central Nod that acts to oligomerize these
proteins, and carboxyl-terminal LRRs that are required to de-
tect specific PAMPs and is involved in autoregulation of NLR
activity (3). These proteins have a remarkable structural simi-
to play key roles in pathogen defense through sensing bacteria
and generating immune responses (5).
Recognition of microbes by NLRs
Nod1/CARD4 senses the presence of bacterial pathogens, such
as Shigella flexneri (6), enteroinvasive Escherichia coli (7),
Pseudomonas aeruginosa (8), and Helicobacter pylori (9, 10),
through the recognition of peptidoglycan (PGN) molecules
that contain meso-diaminopimelic acid (meso-DAP) (11).
Gram-negative and only specific Gram-positive bacteria (12).
Department of Pathology and Comprehensive Cancer Center, University of Michigan
Medical School, Ann Arbor, MI 48109
Received for publication May 22, 2006. Accepted for publication June 20, 2006.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
1This work was supported by National Institutes of Health Grants AI063331, AI064748,
DK61707, and DK067628 and a grant from the Eli and Edythe L. Broad Foundation (to
G. N.). Other support includes a fellowship from Fondazione Italiana Ricerca sul Cancro (to
L.F.), a Career Development Award from the Crohn’s and Colitis Foundation of America
(to C.M.), and Grant T32/HL007517 from the National Institutes of Health (T.-D.K.).
2Address correspondence and reprint requests to Dr. Gabriel Nu ´n ˜ez, Department of Pa-
East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: email@example.com
3Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; Nod,
nucleotide-binding oligomerization domain; CARD, caspase-recruitment domain; LRR,
leucine-rich repeat; ASC, apoptosis-associated speck-like protein containing a CARD;
MDP, muramyl dipeptide; NLR, Nod-like receptor; PGN, peptidoglycan; DAP, diamin-
opimelic acid; iE-DAP, ?-D-glutamyl-meso-DAP; IKK, I?B kinase; CD, Crohn’s disease;
BS, Blau syndrome; FCAS, familial cold autoinflammatory syndrome.
Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00
tation: effect on long-term outcome is confirmed in 2 independent cohorts and may be
modulated by the type of gastrointestinal decontamination. Blood 107: 4189–4193.
58. Miceli-Richard, C., S. Lesage, M. Rybojad, A. M. Prieur, S. Manouvrier- Hanu,
mutations in Blau syndrome. Nat. Genet. 29: 19–20.
59. Kanazawa, N., I. Okafuji, N. Kambe, R. Nishikomori, M. Nakata-Hizume, S. Nagai,
A. Fuji, T. Yuasa, A. Manki, Y. Sakurai, et al. 2005. Early-onset sarcoidosis and
CARD15 mutations with constitutive nuclear factor-?B activation: common genetic
etiology with Blau syndrome. Blood 105: 1195–1197.
60. Hysi, P., M. Kabesch, M. F. Moffatt, M. Schedel, D. Carr, Y. Zhang, B. Boardman,
E. von Mutius, S. K. Weiland, W. Leupold, et al. 2005. NOD1 variation, immuno-
globulin E and asthma. Hum. Mol. Genet. 14: 935–941.
61. Weidinger, S., N. Klopp, L. Rummler, S. Wagenpfeil, N. Novak, H. J. Baurecht,
W. Groer, U. Darsow, J. Heinrich, A. Gauger, et al. 2005. Association of NOD1
polymorphisms with atopic eczema and related phenotypes. J. Allergy Clin. Immunol.
62. Holt, P. G., and P. D. Sly. 2002. Interactions between respiratory tract infections and
atopy in the aetiology of asthma. Eur. Respir. J. 19: 538–545.
63. Dowds, T. A., J. Masumoto, F. F. Chen, Y. Ogura, N. Inohara, and G. Nunez. 2003.
Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever
gene product. Biochem. Biophys. Res. Commun. 302: 575–580.
induced interleukin 1? secretion in monocytic cells: enhanced activity of
disease-associated mutants and requirement for ASC. J. Biol. Chem. 279:
65. Agostini, L., F. Martinon, K. Burns, M. F. McDermott, P. N. Hawkins, and
J. Tschopp. 2004. NALP3 forms an IL-1?-processing inflammasome with in-
creased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:
66. Hoffman, H. M., S. Rosengren, D. L. Boyle, J. Y. Cho, J. Nayar, J. L. Mueller,
J. P. Anderson, A. A. Wanderer, and G. S. Firestein. 2004. Prevention of cold-asso-
ciated acute inflammation in familial cold autoinflammatory syndrome by interleu-
kin-1 receptor antagonist. Lancet 364: 1779–1785.
3513The Journal of Immunology