The different roles of innate immune receptors in inflammation and carcinogenesis between races
Yamaguchi et al. Environmental Health and Preventive Medicine
The different roles of innate immune receptors in inflammation and carcinogenesis between races
Natsu Yamaguchi 0
Yoshimi Suzuki 1
M. H. Mahbub 0
Hidekazu Takahashi 0
Ryosuke Hase 0
Yasutaka Ishimaru 0
Hiroshi Sunagawa 0
Rie Watanabe 0
Yoshinobu Eishi 1
Tsuyoshi Tanabe 0
0 Department of Public Health and Preventive Medicine, Graduate School of Medicine, Yamaguchi University , 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505 , Japan
1 Department of Human Pathology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University , Tokyo , Japan
Innate immune factors exert widespread effects on cytokine secretion, cell survival, autophagy, and apoptosis. Nucleotide-binding and oligomerization domain-like receptors (NLRs) are members of the innate immune system in the cytosol that sense pathogens, endogenous danger molecules such as uric acid, and pollutants. Nucleotidebinding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) are components of NLR family, and ligands of these factors are γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP), respectively. Upon recognition of ligands, NOD1 and NOD2 induce the production of inflammatory cytokines and transcription factors including interleukin-6 (IL-6) and nuclear factor-κB (NF-κB). We examined the function of NOD1 and NOD2 in innate immunity, with a focus on their differing roles in disease pathogenesis between Japanese and Caucasian populations. Susceptibility to several immune-related diseases, including Crohn's disease, colorectal and breast cancers, and graft-versus-host-disease (GVHD) showed a correlation with genetic variants of NOD2 in Caucasian, but not in Japanese, populations. This difference may be primarily due to the fact that three major NOD2 SNPs (R702W, G908R, L1007insC) prevalent in Caucasians are rare or absent in Japanese populations. Because NLR has diverse effects on immune function, it is possible that many as yet uncharacterized immune-related diseases will also show different susceptibilities between races due to the different ratio of genetic variants in innate immune genes.
TLR; NOD; Crohn's disease; Sarcoidosis
Two types of immune mechanisms, innate system and
adaptive system, are used to eliminate the invading
pathogens, endogenous danger molecules, and pollutants. As
a first step of immune system, innate immune responses
are mediated by a set of non-clonal, germline-encoded
pattern-recognition receptors (PRRs) that sense
conserved pathogen-associated molecular patterns (PAMPs)
in pathogens and danger-associated molecular patterns
(DAMPs). PAMPs include flagellin, single RNA,
unmethylated CpG DNA, and lipopolysaccharides.
DAMPs consist of endogenous factors such as fatty
acids, heat shock proteins (HSP), and uric acid. Recent
studies revealed that PRPs also recognize pollutants
including asbestos [
] and PM2.5 [
]. Various PRRs exist
in the extracellular space, integrated in cellular
membranes, and in the cytosol. The toll-like receptors (TLRs)
were first identified as genes that determine body axis.
They represent a class of membrane-bound PRRs that
respond to PAMPs and DAMPs at the cell surface and
within endosomes [
] (Fig. 1). The nucleotide-binding
oligomerization domain (NOD)-like receptor (NLR)
family consists of cytoplasmic PRRs that play a pivotal
role in sensing PAMPs and DAMPs in the cytosol [
The NLR family consists of more than 20 cytosolic
proteins that are characterized by the presence of a
conserved tripartite domain structure: C-terminal
leucine-rich repeats (LRRs) that are involved in sensing
of ligands, a central NOD domain, and an N-terminal
NOD1 CARD NOD
NOD2 CARD CARD NOD
NLRP3 PYD NOD
HSP, Fatty Acid
C(IyLt-o6k,iNneFs-B,t)ranscription factors IAnpfloapmtomsaistion,
Induction of acquired immunity
Fig. 1 Innate immune receptors, NLRs and TLRs. The main members of the innate immune system are NLRs (membrane binding) and TLRs (in
the cytosol). NLRs and TLRs sense intracellular and extracellular PAMPs, respectively. The subsequent activation of inflammatory cytokines
including IL-6 and NF-κB results in the inflammation, apoptosis, and autophagy. These pathways are involved in the induction of
effector-binding domain, such as the Pyrin domain
(PYD) and the caspase recruitment domain (CARD) [
NOD1 and NOD2
NOD1 and NOD2 are members of the NLR family with
an N-terminal CARD domain (Fig. 2). In early studies,
NOD1 and NOD2 were found to induce nuclear
factorκB (NF-κB) activation when overexpressed in
mammalian cells and to eliminate pathogens independently of
]. The ligand for NOD1 is
γ-D-glutamyl-mesodiaminopimelic acid (iE-DAP) found in many
gramnegative and certain gram-positive bacteria [
ligand, NOD2 recognizes muramyl dipeptide (MDP), a
component of peptidoglycan that is present in both
gram-positive and gram-negative bacteria [
]. Nod1 and
Nod2 undergo conformational changes upon recognition
of ligands, resulting in self-oligomerization via the
central NOD domain and binding to receptor-interacting
protein (RIP)-like interacting caspase-like apoptosis
regulatory protein kinase (RICK, RIP2), a serine
threonine kinase that leads to NF-κB activation [
]. The tissue
distribution patterns of NOD1 and NOD2 are quite
different. Expression pattern of Nod1 is ubiquitous in
various tissues and Nod2 is restrictedly expressed in the
Paneth cells of the small intestine and monocytes [
vivo studies have revealed that NOD1 ligands simulate
chemokine production and recruitment of neutrophils
] and contribute to adaptive immune responses.
Crohn’s disease (CD) is characterized by recurring
inflammation in the gastrointestinal tract. We reported the
association between genetic polymorphisms of NOD2
and susceptibility to CD in Caucasians [
] (Fig. 2). The
genetic variants of NOD2 found in about 10% of CD
patients, including three common mutations that involve
amino acid residues in NOD domain (R702W) or within
LRRs (G908R and L1007insC) of Nod2, showed
association with the development of CD. Ethnic differences in
the genetic susceptibility to CD have been reported
between Caucasian and Asian populations. Several studies
revealed that none of the three common NOD2 variants
that have been associated with CD in Caucasians are
present in Japanese [
], Chinese [
], and Korean [
CD patients. Also, a systemic genomic screening of the
entire coding region of NOD2 in a Japanese CD
population showed no common genetic variants [
results apparently indicate that the NOD2 gene is not a
major contributor to CD susceptibility in Asian
population. Our functional analysis showed that CD-associated
mutations lead to the reduction (R702W, G908R) or loss
(L1007insC) of NF-κB activation upon MDP stimulation,
compared with the wild-type NOD2 [
The plausible mechanism to explain the association
between mutants of NOD2 and susceptibility to CD was
estimated by constructing NOD2-deficient mice [
The mice showed that the NOD2 protein is a key
regulator of immunity within the intestine. These animals
failed to recognize bacterial muramyl dipeptide and were
susceptible to bacterial infections through the oral route
but not via the peritoneal or intravenous route. Further,
it turned out that NOD2 was necessary to express
defensins, a subgroup of intestinal anti-microbial peptides.
The estimated hypothesis was that the dysfunction of
NOD2 may lead to facilitated entry of bacteria into
epithelial cells through defective regulation of defensin
expression, leading to an abnormal inflammatory response
to uncleared bacteria.
Blau syndrome (BS) and early-onset sarcoidosis (EOS)
BS is a rare autosomal dominant disease characterized
by early-onset granulomatous inflammation including
uveitis, arthritis, and dermatitis with camptodactyly [
Because BS susceptibility locus has been identified at
16p12 to which coincides with that of NOD2, genetic
screening of NOD2 were performed in families with BS
]. BS families shared three missense mutations
(R334Q, L469F, and R334W) in NOD2 (Fig. 2). We
analyzed the function of these mutations and found that all
of them augmented NOD2 basal activity, even in the
absence of the ligand MDP [
], and further enhanced
NOD2 activity by addition of MDP. Thus, the genetic
variants in NOD2 associated with BS function as
hyperresponsive mutations, which is consistent with the
dominant mode of inheritance of the granulomatous disease.
EOS is a systemic granulomatous syndrome sharing
the distinct triad of skin, joint, and eye inflammation
with BS and is progressive and causes severe
complications, such as destructive arthropathy and blindness.
Systemic analysis of NOD2 genes of the EOS cases in
Japanese population also showed the same mutations as
in BS [
]. Thus, EOS shares a common genetic etiology
of NOD2 with BS.
Sarcoidosis, a chronic systemic granulomatous disease of
unknown cause, may result from the exposure of
genetically susceptible subjects to a specific environmental
agent(s). The only bacterium to be isolated from sarcoid
lesions to date is Propionibacterium acnes (P. acnes)
]. We found that both NOD1 and NOD2 proteins
recognize intracellular P. acnes. Systematic search for
NOD1 gene polymorphisms in Japanese sarcoidosis
patients identified significant elevation of G796A in
sarcoidosis patients (Fig. 2). Genetic screening of the
NOD2 gene in sarcoidosis revealed no common
mutations in Japanese and Caucasian subjects [
Our functional analysis revealed that the NOD1 G796A
was associated with lower expression in protein level
leading to reduced NF-κB activation in response to
intracellular P. acnes . These results indicate that
impaired recognition of intracellular P. acnes through
NOD1 variant causes the susceptibility to sarcoidosis in
the Japanese population.
Mutations in the NOD2 gene associated with Crohn’s
disease have also been associated with an increased risk
for the development of different types of cancer
(Helicobacter pylori-induced MALT lymphoma, colonic
adenocarcinoma, and breast and lung cancer) in Caucasians
]. In Japanese populations, we revealed that a
NOD2 SNP in the NOD domain (R471C) has been
associated with acute myeloid leukemia (AML) but not with
acute lymphoblastic leukemia [
] (Fig. 2). This
difference may be explained by the results of recent studies
that revealed an important role of NOD2 in the
differentiation of bone marrow CD34+ hematopoietic cells, by
mediating the induction of cytokines indispensable for
cell differentiation toward the myeloid lineage [
]. It is
possible that the NOD2 variant causes abnormal cell
differentiation by altering cytokine production, thus leading
to the elevated incidence of AML. There are several
possible mechanisms that may account for the contribution
of NOD2 to the risk of malignant diseases. Impairment
of the innate immune system by NOD2 variants may
induce chronic activation of alternate recognition
receptors, such as the TLR, which can also lead to NF-κB
activation and pro-inflammatory cytokine release,
possibly provoking the
inflammation-dysplasiacarcinoma sequence [
]. In addition to its role in the
non-specific innate immune system, NOD2 may
generate signals for the adaptive immune response, through
cytokine release, leading to the activation of dendritic
cells and the promotion of T cell differentiation. NOD2
variants may impair the adaptive immune system in
evoking anti-tumor immunity [
Graft-versus-host disease (GVHD)
Several recent studies in Caucasian patients have
described a significant correlation between the severity
of acute GVHD and the presence of three NOD2 SNPs:
R702W, G908R, and L1007insC. Holler et al. reported
an increased incidence and severity of acute GVHD
associated with the presence of NOD2 SNPs in two
separate patient cohorts [
]. In contrast, Granell et al.
demonstrated that in a T cell-depleted setting, these
SNPs had no effect on acute GVHD . In our analysis
in a severe GVHD Japanese patient group, no genetic
alteration of NOD2, including the three major SNPs
seen in Caucasians, were found [
]. Previous studies
have shown that Japanese and Swedish patient
populations have a lower probability of acute GVHD
]. No dysfunctional NOD2 variants were found in the
severe acute GVHD group that may explain the
differences in the occurrence of acute GVHD among different
We discussed the physiology of NLR-related diseases
and ethnic differences between Caucasians and Japanese.
The three mutations of NOD2 cause increased
susceptibility to Crohn’s disease and several other malignant
diseases, including colorectal and breast cancers in
Caucasians, but the Japanese population lacks the
NOD2 mutations. Because NLR exerts widespread
effects on cytokine secretion, cell survival, autophagy,
and apoptosis, it is possible that many as yet
uncharacterized diseases will also show differences in
susceptibility between races.
AML: Acute myeloid leukemia; BS: Blau syndrome; CARD: Caspase recruitment
domain; CD: Crohn’s disease; DAMPs: Danger-associated molecular patterns;
EOS: Early-onset sarcoidosis; GVHD: Graft-versus-host-disease; iE-DAP:
γ-D-glutamyl-meso-diaminopimelic acid; IL-6: Interleukin-6; MDP: Muramyl
dipeptide; NF-κB: Nuclear factor-κB; NLRs: Nucleotide-binding and oligomerization
domain-like receptors; NOD1 and NOD2: Nucleotide-binding oligomerization
domain-containing protein 1 and 2; P. acnes: Propionibacterium acnes;
PAMPs: Pathogen-associated molecular patterns; PYD: Pyrin domain;
RICK: Receptor-interacting protein-like interacting caspase-like apoptosis regulatory
protein kinase; RIP: Receptor-interacting protein; TLRs: Toll-like receptors
Availability of data and materials
Not applicable, since this is a review-type manuscript.
NY and TT carried out the summarization and description of this manuscript.
YS and YE contributed the sarcoidosis section. HT contributed the GVHD
section. RH, YI, and HS contributed the malignant disease section. NY and
MM contributed the Crohn’s disease and Blau syndrome section. All authors
read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable, since this is a review-type manuscript.
Consent for publication
The authors declare that they have no competing interests.
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