REVIEW
Role of mammalian chitinases in inflammatory conditions
Mayumi Kawada1, Yuriko Hachiya1, Atsuko Arihiro1, and Emiko Mizoguchi1, 2Gatrointestinal Unit, Department of Medicine, 2Center for the Study of Inflammatory Bowel
Disease, Massachusetts General Hospital, Harvard Medical School,
Boston, MA, U.S.A.

1(Received for publication on November 9, 2006)(Revised for publication on January 27, 2007)(Accepted for publication on February 15, 2007)

Abstract. It has been hypothesized that dysregulated host/microbial interactions play apivotal role in the pathogenesis of inflammatory bowel disease. However, the exact mechanisms underlying the induction and perpetuation of the intestinal disorder are unclear. Recently, we unexpectedly discovered significantly upregulated gene expression of chitinase
3-like-1 in inflamed colon of the dextran sulfate sodium-induced colitis model by employing
the DNA-microarray analysis. Chitinase 3-like-1 has a chitin binding ability, but lacks the
enzymatic activity of lysing microbial cell wall. Chitinase 3-like-1 protein is mainly expressed in colonic epithelial cells and macrophages in the inflamed colon of dextran sulfate
sodium-induced colitis. Chitinase 3-like-1, which can be upregulated after pro-inflammatory
cytokine stimulation, possesses an ability to enhance the adhesion and internalization of
intracellular bacteria into colonic epithelial cells. Most importantly, in vivo neutralizationof chitinase 3-like-1 significantly suppressed the development of dextran sulfate sodiuminduced colitis by dramatically decreasing the bacterial adhesion and invasion into colonicepithelial cells. Furthermore, anti-chitinase 3-like-1 antibody-treated mice exhibited a significantly lower load of Salmonella typhimurium in peripheral organs as compared to control
rabbit IgG-treated mice. Recently, it has been reported that acidic mammalian chitinase isexpressed in the setting of T helper-2-associated inflammation and subsequently induces
airway hyperresponsiveness in allergic asthma patients. In addition, pan-chitinase inhibitor significantly ameliorates T helper-2-mediated inflammation and airway hypersensitivity.
These studies provide to be a novel insight into the physiological role of mammalian chitinases in host/microbial interactions, and inhibition of chitinase activity would be considered anovel therapeutic strategy of allergic and inflammatory disorders. (Keio J Med 56 (1) : 21－ 27,
March 2007)
Key words: acidic mammalian chitinase, chi-lectin, chitinase 3-like-1, enteric bacteria, inflammatory
bowel disease
Abbreviations used in this paper: Ab, antibody; AIEC, adherent invasive Escherichia coli; AMCase,
acidic mammalian chitinase; APC, antigen presenting cell; CBM, carbohydrate-binding module; CBP,
chitin-binding protein; CD, Crohn’s disease; CECs, colonic epithelial cells; CHI3L1, chitinase 3-like-1;
CLPs, chitinase-like proteins; DSS, dextran sulfate sodium; ECM, extracellular matrix; GlcNAc, N-acetylglucosamine; IBD, inflammatory bowel disease; IGF, insulin-like growth factor; IL, interleukin; KO,knockout; MAP, mitogen-activated protein; MCP, monocyte chemoattractant protein; MMP, metalloproteinase; PI-3K, phosphoinositide kinase-3; SI, stabilin-1-interacting; Th, T helper; UC, ulcerative colitis

Reprint requests to: Emiko Mizoguchi, M.D., Ph.D., Division of Gastroenterology, GRJ-702, Massachusetts General Hospital, 55 Fruit Street, Boston, MA
02114, U.S.A., E-mail: emizoguchi@partners.org
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Kawada M et al: Mammalian chitinases in inflammation

22

Introduction
Inflammatory bowel disease (IBD), consisting of
Crohn’s disease (CD) and ulcerative colitis (UC), is achronic, relapsing and remitting, inflammatory condition that affects individuals throughout their lives.1 Although the pathogenesis of IBD is still unknown, it has
been widely accepted that genetic and environmental
factors and immunological abnormalities are involvedin this pathogenesis. Recent clinical and experimental
studies have shown that impaired intestinal barrier function permits penetration of harmful molecules into theunderlining colonic lamina propria and initiates and/or
perpetuates the intestinal inflammation.2 Abrogation oforal tolerance to normal enteric flora is thought to be important in T helper type 1 (Th1)-mediated experimental
colitis models.3 In fact, some commensal bacteria havebeen postulated to be associated with the development of
IBD.4, 5 However, the factors that are actually involved in
the host/microbial interaction have remained to be identified.
DNA-microarray analysis has been used widely as a
powerful approach to identify novel and unexpected molecules associated with inflammation.6 By utilizing thisapproach, we have found that chitinase 3-like 1 (CHI3L1
also known as YKL40 or HC-gp39), which interacts
with a carbohydrate polymer (chitin), is involved in theexacerbation of intestinal inflammation by enhancing thebacterial/CEC interaction.6
In the last few years, there have been a growing number of publications concerning chitinases and chitinaselike molecules including CHI3L1. Amino acid sequence
analysis reveals that CHI3L1 belongs to the glycohydrolase family 18,7 but the complete characterization of
the in vivo biological functions of CHI3L1 remains to beestablished. We herein review potentially important rolesof mammalian chitinases, including CHI3L1, in immune
responses under inflammatory conditions, and discuss
the potential novel therapeutic strategy of anti-chitinases
antibodies.
Mammalian chitinases
More than one billion tons per year of chitin, a polymerof β-1, 4-N-acetyl-glucosamine (GlcNAc), are producedby almost all living organisms including insects; fungi;
crustaceans; and other marine organisms, but not by
mammals.8 Despite its strong resistance against chemicals, insolubility, and abundant production, chitin does
not accumulate in most ecosystems, suggesting that chitin is degraded by efficient processes in nature. In fact,chitin is degraded by chitinases (EC 3.2.1.14) that belong
to members of the glycohydrolase family 18. This family
that is characterized by an eight-fold α/β barrel struc-ture includes bacterial as well as plant chitinases. 9 In
addition to being important for energy exchange, chitin
degradation is essential in a variety of biological processes. For example, chitin-containing organisms produce
chitinases to remodel their structures.10 Plants are known
to produce chitinases to protect themselves from damage
by chitin-containing microorganisms such as fungi.8
Chitinases have been generally considered to lack inmammalian bodies due to the absence of chitin. However, recent studies have identified chitinases and chitinaselike proteins (CLPs) belonging to the glycohydrolase
family 18 in mice and human. The members of mammalian chitinases and CLPs include chitinase 3-like-1(CHI3L1),1 1 chitotriosidase,1 2 YKL-39,1 3 Ym1,1 4 acidic
mammalian chitinase (AMCase), 1 5 oviduct-specificglycoprotein1 6 and stabilin-1-interacting chitinase-likeprotein.17 Chitotriosidase and AMCase possess chitinase
enzymatic activity, whereas other mammalian chitinases,
including CLPs, do not possess this activity.1 8 Mammalian chitinases with enzymatic activity have a chitinbinding domain that contains six cysteine residues responsible for their binding to chitin.19 In contrast, CLPs
do not contain such typical chitin-binding domains, but
still can bind to chitin with high affinity.17
Chitinase 3-like-1
Chitinase 3-like protein 1 is a 40 kDa mammalian
glycoprotein. 1 1, 2 0, 2 1 The gene for CHI3L1 is locatedon chromosome 1q31-q32, and consists of 10 exonsand spans about 8 Kb of genomic DNA. 2 1 CHI3L1
is produced by human synovial cells, 2 2 osteosarcoma
cells, 2 0 chondrocytes, 1 1 smooth muscle cells, 2 3 macrophages,2 4 neutrophils,2 5 colonic epithelial cells6 andothers. CHI3L1 is related to several other “mammalian
CLPs”: chitotriosidase,12 YKL-39,13 Ym1,14 AMCase,15
oviduct-specific glycoprotein16 and stabilin-1-interacting(SI)- CLP.17 These mammalian chitinases possess a conserved sequence motif (DXXDXDXE) on strand β4, andcatalytic activity in these chitinases is mediated by theglutamic acid (E), which protonates the glycosidic bondwith chitin.26 AMCase and chitotriosidase have catalytic
activity but CHI3L1, YKL-39, Ym1, oviductin, SI-CLP
do not have this activity.17 Due to the substitution of an
essential glutamic acid residue to leucine,11 CHI3L1 has
no chitinase activity,1 1 but still can bind to chitin andchito-oligosaccharides with high affinity through a preserved hydrophobic substrate binding cleft.24, 27 CHI3L1
also interacts with glycosaminoglycans such as heparinand hyaluronan.23, 28 The putative heparin-binding site is
GRRDKQH (residues 143-149).2 7 Furthermore, Bigg etal. have recently reported an ability of CHI3L1 to bindto collagen type 1, 2 and 3.29 CHI3L1 has therefore been
defined as a CLP or chitinase-like lectin (Chi-lectin)28

Keio J Med 2007; 56 (1): 21－ 27

What is the physiological function of CHI3L1?
The physiological and biological functions of CHI3L1
are still unclear. However, the studies regarding arthritis,
cancer, and liver fibrosis1 1, 2 5, 3 0, 3 1 suggest that CHI3L1
plays an important role in the processes of inflammationand tissue remodeling. Although CHI3L1 is not synthesized under state of health, an induction of this protein
expression is observed in the patients with rheumatoid
arthritis and IBD/colorectal carcinoma.3 2 This observation suggests that CHI3L1 expression is induced under
several inflammatory and malignant conditions. Recklies et al.33 reported that CHI3L1 increases growth rates
of fibroblasts by synergistically working with IGF-1(insulin-like growth factor-1) in growth stimulation.
CHI3L1 possesses abilities to activate mitogen-activatedprotein (MAP) kinase and phosphoinositide kinase-3(PI-3K) signaling cascades in fibroblasts to control mitogenesis.33 Recently, Ling et al.34 showed that stimulation of human articular chondrocytes or skin fibroblasts
with CHI3L1 suppresses the cytokine-induced secretionof metalloproteinase (MMP)-1, MMP-3, MMP-13 andthe chemokine IL-8. This finding suggests that CHI3L1
elicits an anti-catabolic effect preserving extracellularmatrix (ECM) during tissue remodeling/destruction.3 4
Our group demonstrated that CHI3L1 stimulation significantly activates NF-kB transcription in human colon
cell lines and enhances the production of TNFα, IL-8,
RANTES and eotaxin.3 5 These findings suggest that
CHI3L1 may play a crucial role in the pathogenesis ofcolitis by enhancing the production of proinflammatory
cytokines and chemokines by CECs.
CHI3L1 in IBD
We have demonstrated that CHI3L1 is expressed by
CECs and lamina propria cells (mainly macrophages)
under several intestinal inflammatory conditions observed in TCRα-and IL-10 knockout (KO) mice as wellas DSS-induced colitis.6 In contrast, the expression of
CHI3L1 is undetectable in colons without colitis. Enhanced CHI3L1 mRNA expression is also detectable inpatients with active but not quiescent IBD (both UC andCD) or normal individuals.6 Interestingly, it has previously been reported that there is a positive correlation
between serum CHI3L1 and C-reactive protein (CRP, amarker for the severity of inflammation) levels in UC patients.36 Therefore, it could be predicted that CHI3L1 is
upregulated in inflammatory conditions, including bothacute and chronic colitis. In fact, endogenous CHI3L1
mRNA level was found to be significantly upregulated
after the stimulation with pro-inflammatory cytokines(TNFα, IL-1βand IL-6) in CEC lines.
To investigate the potential role of CHI3L1 in host/microbial interaction, CHI3L1-overexpressing CEC

23lines were infected with Salmonella typhimurium andadherent invasive E. coli (AIEC). Surprisingly, significantly enhanced adhesion and invasion rates were foundin these two bacteria on CHI3L1-overexpressing cells.
CHI3L1-mediated bacterial adhesion and invasion weresignificantly inhibited by pretreatment with anti-CHI3L1
specific antibody. An AIEC LF82 strain has been characterized as potentially pathogenic bacteria in the colonsof CD patients by the strong and efficient ability in adhesion to and invasion into intestinal epithelial cells andmacrophages.37 In contrast, non-pathogenic E. coli (e.g.,DH5α strain) does not adhere to or invade into CHI3L1
overexpressing CECs. 9 Therefore, it is possible that
CHI3L1 on CECs may specifically enhance the adhesion
and invasion of pathogenic (S. typhimurium) and potentially pathogenic (AIEC) but not non-pathogenic (DH5α) bacteria. These in vitro data are further confirmed
by in vivo experiments; anti-CHI3L1 Ab treatment significantly reduces the translocation of orally inoculated
S. typhimurium to host peripheral tissues (e.g., spleen,mesenteric lymph nodes, and liver) compared to control
rabbit IgG-treated mice.6 In addition, neutralization of
CHI3L1 by anti-CHI3L1 Ab significantly suppressed
DSS-induced acute colitis. 6 Therefore, these results
strongly suggest that CHI3L1 on CECs possesses theability to enhance the adhesion and invasion of intracellular bacteria and acts as a pathogenic mediator of intestinal inflammation.
Possible role of chitin-binding proteins (CBPs) inbacteria/CECs interaction
Plant chitinases have been shown to possess anti-fungal and anti-viral effects through the binding to chitin.38
The chitin-binding domain of plant chitinases efficiently
interacts with as well as digests chitin-containing organisms.39 Interestingly, the chitin-binding domain is structurally preserved within mammalian CLPs including
CHI3L1. Of note, Vaaje-Kolstad et al. recently demonstrated that a gram-negative bacterium, Serratia marcescens, expresses a chitin-binding protein, CBP21, which
enhances chitin accessibility to bacterial chitinases.4 0
CBP21 is 18 kDa protein with a structure consisting of athree-stranded and a four-stranded β-sheet that forms a
β-sandwich.40 Through the sequence similarity, CBP21
is classified as a part of the CBM (carbohydrate-binding
module) family 331 3 and identified to possess a chitinbinding domain. Within the 80 CBP sequences present
in the Pfam database, 19 other bacterial CBPs cluster
within CBP21. A multiple alignment revealed 40 highly
conserved residues (>90% conserved) and a cluster ofconserved, mainly hydrophilic, residues at the surface of
CBP21.40 Importantly, the majority of chitinase-producing pathogenic microorganisms contain a gene encoding
for the homologue of the cbp21 gene, suggesting the24

Kawada M et al: Mammalian chitinases in inflammation

Fig. 1 Schematic representation of the mechanism of chitinases mediated airway hyperresponsiveness and airway
inflammation. Antigen presenting cells such as dendritic cells (DC) actively uptake antigens (presumably contain chitin) and present
these antigens to Th2 type of CD4＋ T cells. These cells produce Th2 cytokines such as IL-4, IL-5 and IL-13. Of note, IL-13 plays amajor role to induce the production of mammalian chitinases including acidic mammalian chitinase (AMCase) by airway epithelial
cells and macrophages, which express IL-13 receptor (IL-13R) on their surface. AMCase induces the production of monocyte
chemoattractant protein-1 (MCP-1) and eotaxin-1, which induce the recruitment of T cells, eosinophils and macrophages in thelung and further exacerbates the inflammation and airway hyperresponsiveness. Anti-AMCase Ab and chitinase inhibitor efficiently
suppress both airway hyperresponsiveness and inflammation.

presence of a potential binding ability of chitinase-producing pathogenic bacteria to chitin via CBP21 homologue.41 Therefore, it is possible that CHI3L1 may bindto a complex of chitin/CBP that is formed on bacteria
and this binding may subsequently enhance the adhesion
and invasion of these bacteria to CECs. Our group is currently investigating this possibility.
Role of other mammalian chitinases in inflammation
including AMCase and Ym-1
T helper (Th) -2-associated inflammation was originally thought serve as a means to combat parasitic
infections, whereas allergy, including atopic asthma,arises as a consequence of poorly controlled Th2-type
immune responses elicited independently of parasitic
infection.4 2 It has been demonstrated that AMCase andYm1 are specifically upregulated in response to Th2mediated inflammation in the lung.43 As shown in Fig 1,
a Th2-specific, interleukin- (IL)-13-mediated inductionof AMCase by airway epithelial cells and macrophages
may underlie the development of airway hyperresponsiveness and inflammatory cell infiltration after exposure
to an allergen in asthma patients and murine models ofasthma.4 3 Expression of AMCase in the lung epithelial
cells induces the production of monocyte chemoattractant protein (MCP-1) and eotaxin-1, and subsequently
contributes to the pathogenesis of asthma 4 3 [Fig 1].
Allosamidine (pan-chitinase inhibitor) significantly
ameliorates Th2 inflammation and airway hypersensitivity, in part by inhibiting IL-13 pathway activation andchemokine production.43 Therefore, chitinases have been
proposed as a potential therapeutic target in Th2-mediated inflammation.4 3 Moreover, Homer et al.4 4 showedin two different models of Th2 inflammation that Ym1
and AMCase are exclusively expressed in proximal anddistal airway epithelium, respectively. Ym1 is a protein
found to be synthesized by and secreted from murine
activated peritoneal macrophages through oral infection
with nematodes (e.g. Trichinella spiralis).1 8 Interesting-Keio J Med 2007; 56 (1): 21－ 27

25

Fig. 2 Schematic representation of the mechanisms of chitinase 3-like-1 mediated intestinal inflammation. Antigen presenting
cells including dendritic cells and macrophages uptake luminal antigens and produce proinflammatory cytokines including IL-1β,
IL-6 and TNFα. These cytokines bind to their receptors that express on basal side of colonic epithelial cells (CECs) and stimulate
the production of chitinase 3-like-1 (CHI3L1). CHI3L1 actively enhance the adhesion and invasion of pathogenic and potentiallypathogenic bacteria to CECs, and subsequently enhance the exacerbation of intestinal inflammation. Anti-CHI3L1 Ab suppresses bothbacterial adhesion/invasion and intestinal inflammation.

ly, Ramanathan et al.45 reported an increased expressionof AMCase in chronic rhinosinusitis with nasal polyps.
Failure of medical and surgical therapy in chronic rhinosinusitis with nasal polyp is associated with significantly
increased expression of AMCase, which may induce
repeated bacterial infections. These findings suggest that
AMCase may potentially enhance the bacterial interaction, similar to CHI3L1. Therefore, AMCase will be apotentially therapeutic target in chronic rhinosinusitis.
Therapeutic strategy of anti-chitinases in allergic aswell as inflammatory diseases
In combination with studies highlighting the expression of CPLs and AMCase, these studies emphasize thepotential importance of chitinases as critical mediatorsof Th2 responses. Neutralization of AMCase activity
in vivo by administration of anti-AMCase Ab or a panchitinase inhibitor significantly ameliorates airway
inflammation as well as airway hyperresponsiveness.4 3This study suggests that AMCase is a potential therapeutic target that can be manipulated to control asthma andother forms of Th2-mediated inflammation.
Our group also showed that neutralization of CHI3L1
by anti-CHI3L1 Ab significantly suppresses DSSinduced acute colitis.6 To neutralize CHI3L1, we generated anti-CHI3L1 Ab by immunization of rabbits withmouse CHI3L1 peptide 325-339 amino acid residues (nWVGYDDQESVKS/NKVQ-c) that is located within thechitin-binding motif. The immune serum of CHI3L1 antibody was further purified by affinity purification withthe peptide used for the immunization. The specificity ofthis Ab to CHI3L1 protein has been confirmed by ELISA and western blot. Therefore, these studies strongly
suggest neutralization of CHI3L1 as a potential novel
therapeutic approach for IBD by blocking the adhesion
and invasion of intracellular bacteria and by inhibiting
the production of pathogenic mediators (including proinflammatory cytokines and chemokines) [Fig 2].

Kawada M et al: Mammalian chitinases in inflammation

26

Summary
CHI3L1 that is capable of binding to chitin and chitooligosaccharide without a glycohydrolase activity acts asa pathogenic mediator in acute colitis by enhancing theadhesion and invasion of intracellular bacteria to CECs.
Other mammalian chitinases, including AMCase also
possess the ability to exacerbate local inflammation byfacilitating the production of chemical mediators. Therefore, further understanding of the biological roles ofmammalian chitinases would provide intervention to develop novel therapeutic approaches for several diseases
including asthma, chronic rhinosinusitis, and IBD.
Acknowledgements
The authors are grateful to Dr. Deanna Nguyen and Dr.
Atsushi Mizoguchi for their critical comments for thisreview article. This work has been supported by National
Institutes of Health (K08 DK64289 and R03 DK74454),
pilot feasibility study grant of the Center for the Study of
Inflammatory Bowel Disease at Massachusetts General
Hospital (DK43351) and IBD grants from the Eli andEdythe L. Broad Medical Foundation to EM.
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