Immunomodulatory Effects of Chitotriosidase Enzyme

Elmonem, Mohamed A.; van den Heuvel, Lambertus P.; Levtchenko, Elena N.

doi:https://doi.org/10.1155/2016/2682680

Enzyme Research

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Review Article | Open Access

Volume 2016 | Article ID 2682680 | https://doi.org/10.1155/2016/2682680

Immunomodulatory Effects of Chitotriosidase Enzyme

Mohamed A. Elmonem,^1,2Lambertus P. van den Heuvel,^1,3and Elena N. Levtchenko¹

Academic Editor: Qi-Zhuang Ye

Received30 Sept 2015

Accepted16 Dec 2015

Published03 Jan 2016

Abstract

Chitotriosidase enzyme (EC: 3.2.1.14) is the major active chitinase in the human body. It is produced mainly by activated macrophages, in which its expression is regulated by multiple intrinsic and extrinsic signals. Chitotriosidase was confirmed as essential element in the innate immunity against chitin containing organisms such as fungi and protozoa; however, its immunomodulatory effects extend far beyond innate immunity. In the current review, we will try to explore the expanding spectrum of immunological roles played by chitotriosidase enzyme in human health and disease and will discuss its up-to-date clinical value.

1. Introduction

Chitotriosidase enzyme (CHIT1, EC: 3.2.1.14), belonging to the family of 18 glycosyl hydrolases, was the first active chitinase to be discovered in human plasma [1]. Its natural substrate chitin is the second most abundant polysaccharide in nature after cellulose. Chitin is the linear polymer of N-acetylglucosamine and the main component of the cell walls of fungi and protozoa, egg shells of helminthes, and the exoskeletons of arthropods and insects; however, it is completely absent in mammals [2]. Several protein members of the same family were later detected in human plasma and tissues including the enzymatically active acidic mammalian chitinase (AMCase) [3] and chi-lectins, those having a chitin binding domain with no catalytic activity such as chitinase-3 like-1 protein (CHI3L1 or YKL-40), chitinase-3 like-2 protein (CHI3L2 or YKL-39), and oviductal glycoprotein-1 (OVGP1) [4].

In man, chitotriosidase is mainly expressed by different lineages of activated blood and tissue macrophages [5–10] and to a lesser extent by polymorphonuclear leucocytes [11]. The absence of its substrate chitin in the human body and the exclusive production by immunologically active cells immediately elicited the investigation of chitotriosidase involvement in the innate immunity against chitin coated pathogens [12]. Chitotriosidase was confirmed as an essential factor for the defense against many such organisms as Plasmodium falciparum [13], Wuchereria bancrofti [14], Candida albicans [15], Madurella mycetomatis [16], and Cryptococcus neoformans [17].

The role of chitotriosidase enzyme inside macrophages is not limited to its chitinolytic activity against the engulfed chitin containing organisms, or even to innate immunity. It has been implicated in the activation and polarization cascades of macrophages, as well as the indirect activation of other immune cells such as T helper cells and eosinophils [17–19]. Recent studies are interested in its immunomodulatory effects through the processes of chitin recognition, antigen presentation, induction of cell mediated immunity and synergistic effects with proteases, and other enzymes to kill different types of pathogens and cancer cells [10, 17–20]. On the other hand, chitotriosidase has been implicated in the pathogenesis of many human diseases through the improper induction of inflammation and faulty tissue remodeling such as bronchial asthma, chronic obstructive pulmonary disease (COPD), nonalcoholic fatty liver disease, and neurodegenerative disorders like Alzheimer’s disease and amyotrophic lateral sclerosis [19, 21–24].

In the current review, we will provide a summary of basic information about the enzyme and we will discuss its immunomodulatory effects in humans over both innate and acquired immunity together with its current and possible future clinical applications.

2. Genetics

All the genes encoding active chitinases and chitinase-like proteins are clustered in two loci on the human chromosome 1 (1p13 and 1q32). This genetic clustering displays a high degree of conservation among different mammals indicating an evolutionary relationship through common ancestral gene duplication events [4].

The human chitotriosidase gene (CHIT1), extending over 20 kilobases at locus 1q32, consists of 12 exons translating a 466-amino acid protein [5, 25]. A common 24-bp duplication mutation in exon 10 of the CHIT1 gene (Figure 1), leading to alternate splicing and in-frame deletion of 87 nucleotides (29 amino acids), is responsible for almost all detected enzyme deficiencies in different populations when homozygously mutated [25, 26]. Although the mutated 24-bp duplication allele is fairly common in Caucasian individuals (4–6% homozygous and 30–50% heterozygous), it is extremely rare in Sub-Saharan African individuals (0–2% only heterozygous), suggesting the evolutionary advantage of keeping the wild type enzyme in areas with high degrees of endemic parasitic and fungal disease loads [26]. Interestingly, the 24-bp duplication mutation is much more common in the Far East in populations of Japanese, Chinese, and Korean ancestries as almost 30% of them are homozygous, while 50% are heterozygous for the mutation [27, 28].

Other relatively common functional mutations have been also reported in the CHIT1 gene like G102S, G354R, and A442V; however, when homozygously mutated, they are only associated with mild to moderate decrease in enzyme activity [27].

3. Chemistry and Modes of Action

Chitotriosidase enzyme has two major forms (a 50-kilodalton form dominant in blood stream and a 39-kilodalton form dominant in tissues), both having equal chitinolytic activities. The 50-kilodalton protein (466 amino acids) is initially produced by macrophages containing the 39-kilodalton N-terminus having the catalytic domain and the C-terminus having the chitin-binding domain connected together by a short hinge region. The 39-kilodalton protein (387 amino acids) is either cleaved post-translationally in the lysosome of macrophages or less commonly formed through differential RNA processing [25].

The enzyme was initially thought to be an exochitinase because it can hydrolyze chitotriose residues and was termed chitotriosidase based on this observation. However, recent structural and binding modes studies revealed the enzyme to be more of an endochitinase rather than an exochitinase [29, 30]. Furthermore, the strong binding affinity of chitotriosidase to its substrate is also responsible for the relatively high transglycosylation activity of the enzyme even in the absence of excess substrate concentrations, making chitotriosidase a complete independent chitinolytic machinery, and this is in accordance with its anticipated physiological role as a potent immunological defense weapon against microorganisms containing chitin [31, 32].

4. Stimulatory Signals

Although chitotriosidase enzyme is relatively recently linked to human pathology, many aspects of its intracellular and extracellular mechanistic actions, effector and affector molecules, and diseases influenced by the increase or decrease of its expression have been investigated. After its initial association with innate immunity against chitin coated pathogens it was rapidly identified as one of the major protein products of activated macrophages and hence an important nonspecific marker of macrophage activation [12]. Chitotriosidase activity was several hundred-fold elevated in the plasma of patients with the inflammatory based lysosomal storage disorder Gaucher’s disease [1], in which macrophages play an essential role in the clearance of the disease sphingolipid storage material. The lipid laden macrophage becomes the disease histopathological pathognomonic cell in the bone marrow and tissues or what is known as the Gaucher cell. Furthermore, chitotriosidase is significantly elevated in some infections caused by bacterial and viral pathogens lacking its natural substrate chitin [33, 34].

Several intracellular pathways have been proposed to explain the stimulatory molecules and the activation cascades of chitotriosidase enzyme inside human macrophages. Figure 2 provides a simple schematic representation of a macrophage with different proposed stimulatory signals for chitotriosidase expression as well as some of the main intra- and intercellular activities of the enzyme.

Figure 2

Schematic representation of a human macrophage showing different stimuli leading to the increased expression and release of chitotriosidase enzyme. An elaborate description of the processes implicated in increased chitotriosidase expression, as well as its immunological effects, is provided in the text. 39-KD chito: chitotriosidase (39 kilodalton protein); 50KD-chito: chitotriosidase (50 kilodalton protein); ERK1/2: extracellular signal regulated kinases 1/2; IL-1β: interleukin-1β; IL-18: interleukin-18; INF-γ: interferon-gamma; Jak: Janus kinase; LPS: lipopolysaccharide; MAPK: mitogen activated protein kinase; MCP-1: monocyte chemotactic protein-1; MDP: muramyl dipeptide; NF-κB: nuclear factor-kB; NK cell: natural killer cell; NLRP3: NOD-like receptor family, pyrin domain containing 3; NO: nitric oxide; NOD2: nucleotide-binding oligomerization domain-containing protein 2; PI3K: PI3 kinase; PTK: protein tyrosine kinase; RANTES: regulated on activation, normal T cell expressed and secreted; Stat; signal transducers and activators of transcription; TGF-β: transforming growth factor-beta; Th2 cell: T helper type 2 cell; TNF-α: tumor necrosis factor-alpha.

Chitin naturally is a potent activator of chitotriosidase expression, either phagocytized by the macrophage in the cell walls of different fungi and protozoa or directly introduced to macrophages through an unidentified receptor [35, 36]. Chitin and its small hydrolyzed particles when cocultured with macrophages can stimulate the production of TNF-α and IFN-γ [37] which can both increase the expression and activity of chitotriosidase enzyme inside macrophages [38]. Lipopolysaccharide (LPS) which is an important component of the bacterial cell wall was also confirmed as a potent stimulant of chitotriosidase transcription mainly through the NF-κB signaling pathway [38, 39], which is also responsible for exerting the effects of TNF-α; however, IFN-γ most probably produces its effect through stimulating the Jak-Stat signaling pathway [40]. Another possible mechanism of chitotriosidase activation by bacteria is through the bacterial peptidoglycan product muramyl dipeptide (MDP), activating the NOD2 signaling pathway which is also implicated in the expression of chitotriosidase enzyme inside macrophages [41, 42].

Prolactin hormone which is structurally related to many human cytokines and is involved in the regulation of monocyte/macrophage functions was also shown to increase macrophage chitotriosidase production [43]. Through studying signal pathway inhibitors, prolactin was shown to stimulate chitotriosidase expression through multiple signaling pathways including the mitogen activated protein kinase (MAPK), PI3 kinase (PI3K/Akt), and the protein tyrosine kinase (PTK) pathways [44].

The inflammasome system is also expected to play some role in the activation of chitotriosidase expression as both ingested bacterial MDP and cystine crystals can stimulate macrophages through the NLRP3 inflammasome system [45, 46], leading eventually to the production of IL-1β, which either can stimulate the NF-κB signaling pathway directly or indirectly induces the production of TNF-α [47], thus stimulating the expression of chitotriosidase.

Another efficient way to activate macrophages and induce chitotriosidase expression is through the paracrine effect of natural killer cells (NK cells), which when exposed to cells infected with viral, bacterial, or fungal pathogens or even neoplastic cells can produce large amounts of INF-γ and TNF-α [36, 48] in the vicinity of macrophages, both increasing the expression and release of chitotriosidase.

5. Immunological Effects and Clinical Perspectives

Chitotriosidase enzyme expression increases exponentially during the normal monocyte to macrophage maturation process showing a peak of expression between the 5th day and the 7th day of culture [18] and is recently detected to be expressed in both macrophage polarization forms (M1 and M2). M1 macrophages, or classically activated macrophages, are mainly directed to promote inflammation, kill the invading pathogens. and stimulate tissue fibrosis following injury. On the other hand, M2 macrophages, or alternatively activated macrophages, provide regulatory signals to protect the host from an exaggerated inflammatory response and promote tissue remodeling and healing [49]. The fact that chitotriosidase is expressed almost equally in both forms denotes its regulatory roles over processes far beyond the hydrolysis of chitin in pathogens. Further studies are still needed to clarify the role of chitotriosidase enzyme in the alternatively activated M2 macrophages.

Dendritic cells are the most important antigen presenting cells in the human body and one of the members of the monocyte/macrophage lineage. Although AMCase is widely expressed in different tissues, especially in the epithelial cells of the gastrointestinal tract and lungs [3], chitotriosidase was the only implicated active chitinase in the process of chitin recognition and antigen presentation [17]. Recent evidence suggests that the induction of human T helper 2 cells (Th2) in response to pulmonary cryptococcal infection is totally dependent on chitin cleavage by chitotriosidase and that CD11b+ conventional dendritic cells act as antigen presenting cells for the specifically fragmented chitin products [17]. Furthermore, chitotriosidase mRNA and protein concentrations were significantly elevated in mature dendritic cells without chitin sensitization as compared to immature dendritic cells [10], implying that chitotriosidase might be also playing a role in the process of antigen presentation regardless of the presence of chitin.

Recently, activated macrophages and chitotriosidase elevations were implicated in the pathogenesis of nephropathic cystinosis, another lysosomal storage disorder characterized by cystine crystal accumulation inside macrophages in different body organs. Cystine crystals in vitro when incubated with human monocyte derived macrophages were able to activate macrophages in a concentration dependent manner evidenced by the increased concentrations of TNF-α and the concomitant activities of chitotriosidase enzyme in culture supernatant and in cell homogenate. Furthermore, plasma chitotriosidase activities in cystinotic patients correlated positively with leucocytes cystine concentrations, making it a potential target for the disease therapeutic monitoring [50]. Cystinosis was the first crystal based disease with the confirmed involvement of chitotriosidase enzyme in its pathogenesis, making it an interesting target to investigate in other more common crystal related disorders such as gout and hyperoxaluria.

Chitotriosidase also mediates many inflammatory processes through the direct stimulation of different inflammatory mediators such as IL-8, MMP9 (collagenase type IV), MCP-1 (CCL2), RANTES (CCL5), and eotaxin (CCL11), thus increasing the migratory capacity of many immunological cells including T lymphocytes, macrophages, and eosinophils [51, 52]. Levels of chitotriosidase activities strongly correlated with the concentrations of IL-1β and TNF-α in the bronchoalveolar lavage (BAL) of COPD patients supporting the hypothesis of a mutual regulation cascade in the production of these inflammatory mediators [52]. Furthermore, chitotriosidase was involved in the induction of fibrosis in the murine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in mice and significantly enhanced in lungs from Chit1 overexpressing transgenic mice. This effect is explained by the activation of fibroblasts through enhancing TGF-β and increasing the expression of TGF-β receptors 1 and 2 leading to the activation of the Smad and MAPK/ERK signaling pathways [53]. Similar effects have been clinically observed with other human diseases characterized by faulty tissue remodeling and abnormal healing such as nonalcoholic fatty liver disease, bronchial asthma, and diabetic nephropathy in which chitotriosidase plasma activities strongly correlated with disease progression and/or the degree of tissue fibrosis [21, 22, 54]. Targeting the chitotriosidase activation cascade through the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammation and fibrosis in several animal models of autoimmune diseases, most likely by suppressing the chitotriosidase dependent release of different cytokines and chemokines [55]; however, the safety of this approach in humans is not yet determined as it might increase the susceptibility to fungal and protozoal infections.

Chitinases and chi-lectins could play a detrimental role in human cancer development, especially CHI3L1 (YKL-40) which has been associated with increased tumor angiogenesis and bad prognosis in many human neoplasms such as breast, lung, and cervical cancers [56–58]. On the other hand, chitinases are also believed to have some anticancer cell activities [59]. Macrophages were always considered as a primary defense line against neoplastic cells, but the exact mechanisms beyond this action were not very clear [60]. Speculations were made about a combined effect of released NO and H₂O₂; however, there was no much evidence to support this hypothesis [20]. Recently, bacterial and human chitinases were both confirmed as having strong synergistic effects with protease enzymes produced by macrophages to dissolve mucin [61]. This mucolytic activity selectively attacked the altered mucin in the cancer cell wall of animal models and not the healthy cell mucin [59]. It is too early to speculate about the therapeutic applications of this observation as many explanatory mechanistic studies are needed to determine the specificity and the exact molecular and chemical targets of this process.

Chitotriosidase is currently an established or a candidate screening marker, severity marker, and/or therapeutic monitor for over 40 different diseases, inherited and acquired. Table 1 provides a summary of human diseases clinically associated with macrophage activation and chitotriosidase enzyme production. Being a nonspecific marker of macrophage activation and deficient in about 6% of normal population clearly limits chitotriosidase usability as a screening marker for many diseases; however, in established diagnosed nondeficient patients, chitotriosidase is an excellent marker to monitor compliance and response to treatment [62, 63], especially when the treatment targets inflammatory pathways. And in some diseases its marked elevations made it also a quite beneficial screening marker as in Gaucher’s disease even when other lysosomal storage disorders are suspected [64].

6. Conclusions

Being a sensitive biomarker of macrophage activation, chitotriosidase activity is currently more and more commonly used in clinical practice to evaluate the status and response to treatment of inflammatory based diseases in which macrophages play a significant role. The interesting mixture of harmful and beneficial immunological effects made human chitinases and chitotriosidase enzyme an intriguing point of research. If proven safe in humans, the development of targeted therapies either to suppress chitotriosidase activity in autoimmune and inflammatory disorders, or to specifically enhance its targeted activity to kill cancer cells or to potentiate immunity against certain infections will not be far in the future.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

C. E. M. Hollak, S. van Weely, M. H. J. van Oers, and J. M. F. G. Aerts, “Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease,” The Journal of Clinical Investigation, vol. 93, no. 3, pp. 1288–1292, 1994.
View at: Publisher Site | Google Scholar
R. N. Tharanathan and F. S. Kittur, “Chitin—the undisputed biomolecule of great potential,” Critical Reviews in Food Science and Nutrition, vol. 43, no. 1, pp. 61–87, 2003.
View at: Publisher Site | Google Scholar
R. G. Boot, E. F. C. Blommaart, E. Swart et al., “Identification of a novel acidic mammalian chitinase distinct from chitotriosidase,” The Journal of Biological Chemistry, vol. 276, no. 9, pp. 6770–6778, 2001.
View at: Publisher Site | Google Scholar
A. P. Bussink, D. Speijer, J. M. F. G. Aerts, and R. G. Boot, “Evolution of mammalian chitinase(-like) members of family 18 glycosyl hydrolases,” Genetics, vol. 177, no. 2, pp. 959–970, 2007.
View at: Publisher Site | Google Scholar
R. G. Boot, G. H. Renkema, A. Strijland, A. J. Van Zonneveld, and J. M. F. G. Aerts, “Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages,” The Journal of Biological Chemistry, vol. 270, no. 44, pp. 26252–26256, 1995.
View at: Publisher Site | Google Scholar
M. A. Seibold, S. Donnelly, M. Solon et al., “Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit,” Journal of Allergy and Clinical Immunology, vol. 122, no. 5, pp. 944–950, 2008.
View at: Publisher Site | Google Scholar
L. Malaguarnera, M. Di Rosa, A. M. Zambito, N. dell'Ombra, F. Nicoletti, and M. Malaguarnera, “Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease,” Gut, vol. 55, no. 9, pp. 1313–1320, 2006.
View at: Publisher Site | Google Scholar
R. G. Boot, T. A. E. van Achterberg, B. E. van Aken et al., “Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 19, no. 3, pp. 687–694, 1999.
View at: Publisher Site | Google Scholar
M. Di Rosa, D. Tibullo, M. Vecchio et al., “Determination of chitinases family during osteoclastogenesis,” Bone, vol. 61, pp. 55–63, 2014.
View at: Publisher Site | Google Scholar
M. Di Rosa, D. Tibullo, D. Cambria et al., “Chitotriosidase expression during monocyte-derived dendritic cells differentiation and maturation,” Inflammation, vol. 38, no. 6, pp. 2082–2091, 2015.
View at: Publisher Site | Google Scholar
L. Bouzas, J. C. Guinarte, and J. C. Tutor, “Chitotriosidase activity in plasma and mononuclear and polymorphonuclear leukocyte populations,” Journal of Clinical Laboratory Analysis, vol. 17, no. 6, pp. 271–275, 2003.
View at: Publisher Site | Google Scholar
M. van Eijk, C. P. A. A. van Roomen, G. H. Renkema et al., “Characterization of human phagocyte-derived chitotriosidase, a component of innate immunity,” International Immunology, vol. 17, no. 11, pp. 1505–1512, 2005.
View at: Publisher Site | Google Scholar
R. Barone, J. Simporé, L. Malaguarnera, S. Pignatelli, and S. Musumeci, “Plasma chitotriosidase activity in acute Plasmodium falciparum malaria,” Clinica Chimica Acta, vol. 331, no. 1-2, pp. 79–85, 2003.
View at: Publisher Site | Google Scholar
E. H. Choi, P. A. Zimmerman, C. B. Foster et al., “Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India,” Genes and Immunity, vol. 2, no. 5, pp. 248–253, 2001.
View at: Publisher Site | Google Scholar
M. Vandevenne, V. Campisi, A. Freichels et al., “Comparative functional analysis of the human macrophage chitotriosidase,” Protein Science, vol. 20, no. 8, pp. 1451–1463, 2011.
View at: Publisher Site | Google Scholar
P. E. Verwer, C. C. Notenboom, K. Eadie et al., “A polymorphism in the chitotriosidase gene associated with risk of mycetoma due to Madurella mycetomatis mycetoma: a retrospective study,” PLOS Neglected Tropical Diseases, vol. 9, no. 9, Article ID e0004061, 2015.
View at: Publisher Site | Google Scholar
D. L. Wiesner, C. A. Specht, C. K. Lee et al., “Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection,” PLoS Pathogens, vol. 11, no. 3, Article ID e1004701, 2015.
View at: Publisher Site | Google Scholar
M. Di Rosa, G. Malaguarnera, C. De Gregorio, F. Drago, and L. Malaguarnera, “Evaluation of CHI3L-1 and CHIT-1 expression in differentiated and polarized macrophages,” Inflammation, vol. 36, no. 2, pp. 482–492, 2013.
View at: Publisher Site | Google Scholar
K. W. Kim, J. Park, J. H. Lee et al., “Association of genetic variation in chitotriosidase with atopy in Korean children,” Annals of Allergy, Asthma and Immunology, vol. 110, no. 6, pp. 444–449, 2013.
View at: Publisher Site | Google Scholar
X.-Q. Pan, “The mechanism of the anticancer function of M1 macrophages and their use in the clinic,” Chinese Journal of Cancer, vol. 31, no. 12, pp. 557–563, 2012.
View at: Publisher Site | Google Scholar
A. J. James, L. E. Reinius, M. Verhoek et al., “The chitinase proteins YKL-40 and chitotriosidase are increased in both asthma and COPD,” American Journal of Respiratory and Critical Care Medicine, 2015.
View at: Publisher Site | Google Scholar
M. Di Rosa, K. Mangano, C. De Gregorio, F. Nicoletti, and L. Malaguarnera, “Association of chitotriosidase genotype with the development of non-alcoholic fatty liver disease,” Hepatology Research, vol. 43, no. 3, pp. 267–275, 2013.
View at: Publisher Site | Google Scholar
C. Rosén, C. H. Andersson, U. Andreasson et al., “Increased levels of chitotriosidase and YKL-40 in cerebrospinal fluid from patients with Alzheimer's disease,” Dementia and Geriatric Cognitive Disorders Extra, vol. 4, no. 2, pp. 297–304, 2014.
View at: Publisher Site | Google Scholar
A. M. Varghese, A. Sharma, P. Mishra et al., “Chitotriosidase—a putative biomarker for sporadic amyotrophic lateral sclerosis,” Clinical Proteomics, vol. 10, no. 1, article 19, 2013.
View at: Publisher Site | Google Scholar
R. G. Boot, G. H. Renkema, M. Verhoek et al., “The human chitotriosidase gene. Nature of inherited enzyme deficiency,” The Journal of Biological Chemistry, vol. 273, no. 40, pp. 25680–25685, 1998.
View at: Publisher Site | Google Scholar
L. Malaguarnera, J. Simporè, D. A. Prodi et al., “A 24-bp duplication in exon 10 of human chitotriosidase gene from the sub-Saharan to the Mediterranean area: role of parasitic diseases and environmental conditions,” Genes and Immunity, vol. 4, no. 8, pp. 570–574, 2003.
View at: Publisher Site | Google Scholar
P. Lee, J. Waalen, K. Crain, A. Smargon, and E. Beutler, “Human chitotriosidase polymorphisms G354R and A442V associated with reduced enzyme activity,” Blood Cells, Molecules, and Diseases, vol. 39, no. 3, pp. 353–360, 2007.
View at: Publisher Site | Google Scholar
K. H. Woo, B. H. Lee, S. H. Heo et al., “Allele frequency of a 24 bp duplication in exon 10 of the CHIT1 gene in the general Korean population and in Korean patients with Gaucher disease,” Journal of Human Genetics, vol. 59, no. 5, pp. 276–279, 2014.
View at: Publisher Site | Google Scholar
F. Fusetti, H. von Moeller, D. Houston et al., “Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins,” Journal of Biological Chemistry, vol. 277, no. 28, pp. 25537–25544, 2002.
View at: Publisher Site | Google Scholar
K. B. Eide, A. R. Lindbom, V. G. H. Eijsink, A. L. Norberg, and M. Sørlie, “Analysis of productive binding modes in the human chitotriosidase,” FEBS Letters, vol. 587, no. 21, pp. 3508–3513, 2013.
View at: Publisher Site | Google Scholar
L. W. Stockinger, K. B. Eide, A. I. Dybvik et al., “The effect of the carbohydrate binding module on substrate degradation by the human chitotriosidase,” Biochimica et Biophysica Acta, vol. 1854, no. 10, pp. 1494–1501, 2015.
View at: Google Scholar
F. Fadel, Y. Zhao, R. Cachau et al., “New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM,” Acta Crystallographica Section D: Biological Crystallography, vol. 71, no. 7, pp. 1455–1470, 2015.
View at: Publisher Site | Google Scholar
I. Labadaridis, E. Dimitriou, M. Theodorakis, G. Kafalidis, A. Velegraki, and H. Michelakakis, “Chitotriosidase in neonates with fungal and bacterial infections,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 90, no. 6, pp. F531–F532, 2005.
View at: Publisher Site | Google Scholar
Y. G. Kurt, T. Cayci, P. Onguru et al., “Serum chitotriosidase enzyme activity in patients with Crimean-Congo hemorrhagic fever,” Clinical Chemistry and Laboratory Medicine, vol. 47, no. 12, pp. 1543–1547, 2009.
View at: Publisher Site | Google Scholar
Y. Shibata, L. A. Foster, W. J. Metzger, and Q. N. Myrvik, “Alveolar macrophage priming by intravenous administration of chitin particles, polymers of N-acetyl-D-glucosamine, in mice,” Infection and Immunity, vol. 65, no. 5, pp. 1734–1741, 1997.
View at: Google Scholar
C. L. Bueter, C. A. Specht, and S. M. Levitz, “Innate sensing of chitin and chitosan,” PLoS Pathogens, vol. 9, no. 1, Article ID e1003080, 2013.
View at: Publisher Site | Google Scholar
Y. Shibata, W. J. Metzger, and Q. N. Myrvik, “Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: mannose receptor-mediated phagocytosis initiates IL-12 production,” The Journal of Immunology, vol. 159, no. 5, pp. 2462–2467, 1997.
View at: Google Scholar
L. Malaguarnera, M. Musumeci, M. Di Rosa, A. Scuto, and S. Musumeci, “Interferon-gamma, tumor necrosis factor-α, and lipopolysaccharide promote chitotriosidase gene expression in human macrophages,” Journal of Clinical Laboratory Analysis, vol. 19, no. 3, pp. 128–132, 2005.
View at: Publisher Site | Google Scholar
O. Sharif, V. N. Bolshakov, S. Raines, P. Newham, and N. D. Perkins, “Transcriptional profiling of the LPS induced NF-κB response in macrophages,” BMC Immunology, vol. 8, article 1, 2007.
View at: Publisher Site | Google Scholar
K. Schroder, P. J. Hertzog, T. Ravasi, and D. A. Hume, “Interferon-γ: an overview of signals, mechanisms and functions,” Journal of Leukocyte Biology, vol. 75, no. 2, pp. 163–189, 2004.
View at: Publisher Site | Google Scholar
J. P. Boyle, R. Parkhouse, and T. P. Monie, “Insights into the molecular basis of the NOD2 signalling pathway,” Open Biology, vol. 4, no. 12, Article ID 140178, 2014.
View at: Publisher Site | Google Scholar
M. van Eijk, S. S. Scheij, C. P. A. A. van Roomen, D. Speijer, R. G. Boot, and J. M. F. G. Aerts, “TLR- and NOD2-dependent regulation of human phagocyte-specific chitotriosidase,” FEBS Letters, vol. 581, no. 28, pp. 5389–5395, 2007.
View at: Publisher Site | Google Scholar
L. Malaguarnera, M. Musumeci, F. Licata, M. Di Rosa, A. Messina, and S. Musumeci, “Prolactin induces chitotriosidase gene expression in human monocyte-derived macrophages,” Immunology Letters, vol. 94, no. 1-2, pp. 57–63, 2004.
View at: Publisher Site | Google Scholar
M. Di Rosa, A. M. Zambito, A. R. Marsullo, G. Li Volti, and L. Malaguarnera, “Prolactin induces chitotriosidase expression in human macrophages through PTK, PI3-K, and MAPK pathways,” Journal of Cellular Biochemistry, vol. 107, no. 5, pp. 881–889, 2009.
View at: Publisher Site | Google Scholar
F. Martinon, L. Agostini, E. Meylan, and J. Tschopp, “Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome,” Current Biology, vol. 14, no. 21, pp. 1929–1934, 2004.
View at: Publisher Site | Google Scholar
G. Prencipe, I. Caiello, S. Cherqui et al., “Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis,” Journal of the American Society of Nephrology, vol. 25, no. 6, pp. 1163–1169, 2014.
View at: Publisher Site | Google Scholar
K. Lieb, C. Kaltschmidt, B. Kaltschmidt et al., “Interleukin-1β uses common and distinct signaling pathways for induction of the interleukin-6 and tumor necrosis factor α genes in the human astrocytoma cell line U373,” Journal of Neurochemistry, vol. 66, no. 4, pp. 1496–1503, 1996.
View at: Google Scholar
D. Artis and H. Spits, “The biology of innate lymphoid cells,” Nature, vol. 517, no. 7534, pp. 293–301, 2015.
View at: Publisher Site | Google Scholar
M. Di Rosa, G. Malaguarnera, C. De Gregorio, F. D'Amico, M. C. Mazzarino, and L. Malaguarnera, “Modulation of chitotriosidase during macrophage differentiation,” Cell Biochemistry and Biophysics, vol. 66, no. 2, pp. 239–247, 2013.
View at: Publisher Site | Google Scholar
M. A. Elmonem, S. H. Makar, L. van den Heuvel et al., “Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis,” Orphanet Journal of Rare Diseases, vol. 9, no. 1, article 155, 2014.
View at: Publisher Site | Google Scholar
J. Correale and M. Fiol, “Chitinase effects on immune cell response in neuromyelitis optica and multiple sclerosis,” Multiple Sclerosis, vol. 17, no. 5, pp. 521–531, 2011.
View at: Publisher Site | Google Scholar
S. Létuvé, A. Kozhich, A. Humbles et al., “Lung chitinolytic activity and chitotriosidase are elevated in chronic obstructive pulmonary disease and contribute to lung inflammation,” The American Journal of Pathology, vol. 176, no. 2, pp. 638–649, 2010.
View at: Publisher Site | Google Scholar
C. G. Lee, E. L. Herzog, F. Ahangari et al., “Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling,” Journal of Immunology, vol. 189, no. 5, pp. 2635–2644, 2012.
View at: Publisher Site | Google Scholar
M. A. Elmonem, H. S. Amin, R. A. El-Essawy et al., “Association of chitotriosidase enzyme activity and genotype with the risk of nephropathy in type 2 diabetes,” Clinical Biochemistry, 2015.
View at: Publisher Site | Google Scholar
T. E. Sutherland, R. M. Maizels, and J. E. Allen, “Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies,” Clinical and Experimental Allergy, vol. 39, no. 7, pp. 943–955, 2009.
View at: Publisher Site | Google Scholar
R. Shao, Q. J. Cao, R. B. Arenas, C. Bigelow, B. Bentley, and W. Yan, “Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers,” British Journal of Cancer, vol. 105, no. 8, pp. 1203–1209, 2011.
View at: Publisher Site | Google Scholar
X. W. Wang, C. L. Cai, J. M. Xu, H. Jin, and Z. Y. Xu, “Increased expression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesis,” Tumor Biology, vol. 36, no. 2, pp. 901–907, 2015.
View at: Google Scholar
N. Ngernyuang, R. A. Francescone, P. Jearanaikoon et al., “Chitinase 3 like 1 is associated with tumor angiogenesis in cervical cancer,” International Journal of Biochemistry and Cell Biology, vol. 51, no. 1, pp. 45–52, 2014.
View at: Publisher Site | Google Scholar
X. Q. Pan, C. C. Shih, and J. Harday, “Chitinase induces lysis of MCF-7 cells in culture and of human breast cancer xenograft B11-2 in SCID mice,” Anticancer Research, vol. 25, no. 5, pp. 3167–3172, 2005.
View at: Google Scholar
B. Bonnotte, N. Larmonier, N. Favre et al., “Identification of tumor-infiltrating macrophages as the killers of tumor cells after immunization in a rat model system,” Journal of Immunology, vol. 167, no. 9, pp. 5077–5083, 2001.
View at: Publisher Site | Google Scholar
N. N. Sanders, V. G. H. Eijsink, P. S. van den Pangaart et al., “Mucolytic activity of bacterial and human chitinases,” Biochimica et Biophysica Acta—General Subjects, vol. 1770, no. 5, pp. 839–846, 2007.
View at: Publisher Site | Google Scholar
E. Shemesh, L. Deroma, B. Bembi et al., “Enzyme replacement and substrate reduction therapy for Gaucher disease,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD010324, 2015.
View at: Google Scholar
M. Harlander, B. Salobir, M. Zupančič, M. Dolenšek, T. Bavčar Vodovnik, and M. Terčelj, “Serial chitotriosidase measurements in sarcoidosis—two to five year follow-up study,” Respiratory Medicine, vol. 108, no. 5, pp. 775–782, 2014.
View at: Publisher Site | Google Scholar
M. A. Elmonem, D. I. Ramadan, M. S. M. Issac, L. A. Selim, and S. M. Elkateb, “Blood spot versus plasma chitotriosidase: a systematic clinical comparison,” Clinical Biochemistry, vol. 47, no. 1-2, pp. 38–43, 2014.
View at: Publisher Site | Google Scholar
M. Ries, E. Schaefer, T. Lührs et al., “Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C,” Journal of Inherited Metabolic Disease, vol. 29, no. 5, pp. 647–652, 2006.
View at: Publisher Site | Google Scholar
A. C. Vedder, J. Cox-Brinkman, C. E. M. Hollak et al., “Plasma chitotriosidase in male Fabry patients: a marker for monitoring lipid-laden macrophages and their correction by enzyme replacement therapy,” Molecular Genetics and Metabolism, vol. 89, no. 3, pp. 239–244, 2006.
View at: Publisher Site | Google Scholar
E. Dimitriou, M. Cozar, I. Mavridou, D. Grinberg, L. Vilageliu, and H. Michelakakis, “The spectrum of Krabbe disease in Greece: biochemical and molecular findings,” JIMD Reports, 2015.
View at: Publisher Site | Google Scholar
Ž. Reiner, O. Guardamagna, D. Nair et al., “Lysosomal acid lipase deficiency—an under-recognized cause of dyslipidaemia and liver dysfunction,” Atherosclerosis, vol. 235, no. 1, pp. 21–30, 2014.
View at: Publisher Site | Google Scholar
M. Muranjan, S. Agarwal, K. Lahiri, and M. Bashyam, “Novel biochemical abnormalities and genotype in Farber disease,” Indian Pediatrics, vol. 49, no. 4, pp. 320–322, 2012.
View at: Google Scholar
A. Wajner, K. Michelin, M. G. Burin et al., “Comparison between the biochemical properties of plasma chitotriosidase from normal individuals and from patients with Gaucher disease, GM1-gangliosidosis, Krabbe disease and heterozygotes for Gaucher disease,” Clinical Biochemistry, vol. 40, no. 5-6, pp. 365–369, 2007.
View at: Publisher Site | Google Scholar
A. Caciotti, M. Di Rocco, M. Filocamo et al., “Type II sialidosis: review of the clinical spectrum and identification of a new splicing defect with chitotriosidase assessment in two patients,” Journal of Neurology, vol. 256, no. 11, pp. 1911–1915, 2009.
View at: Publisher Site | Google Scholar
C. Tasci, S. Tapan, S. Ozkaya et al., “Efficacy of serum chitotriosidase activity in early treatment of patients with active tuberculosis and a negative sputum smear,” Therapeutics and Clinical Risk Management, vol. 8, pp. 369–372, 2012.
View at: Publisher Site | Google Scholar
O. Coskun, S. Oter, H. Yaman, S. Kilic, I. Kurt, and C. P. Eyigun, “Evaluating the validity of serum neopterin and chitotriosidase levels in follow-up brucellosis patients,” Internal Medicine, vol. 49, no. 12, pp. 1111–1118, 2010.
View at: Publisher Site | Google Scholar
A. Iyer, M. van Eijk, E. Silva et al., “Increased chitotriosidase activity in serum of leprosy patients: association with bacillary leprosy,” Clinical Immunology, vol. 131, no. 3, pp. 501–509, 2009.
View at: Publisher Site | Google Scholar
E. Bargagli, M. Margollicci, A. Luddi et al., “Chitotriosidase activity in patients with interstitial lung diseases,” Respiratory Medicine, vol. 101, no. 10, pp. 2176–2181, 2007.
View at: Publisher Site | Google Scholar
A. Sonmez, C. Haymana, S. Tapan et al., “Chitotriosidase activity predicts endothelial dysfunction in type-2 diabetes mellitus,” Endocrine, vol. 37, no. 3, pp. 455–459, 2010.
View at: Publisher Site | Google Scholar
M. Artieda, A. Cenarro, A. Gañán et al., “Serum chitotriosidase activity is increased in subjects with atherosclerosis disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 9, pp. 1645–1652, 2003.
View at: Publisher Site | Google Scholar
T. Kologlu, S. K. Ucar, E. Levent, Y. D. Akcay, M. Coker, and E. Y. Sozmen, “Chitotriosidase as a possible marker of clinically evidenced atherosclerosis in dyslipidemic children,” Journal of Pediatric Endocrinology and Metabolism, vol. 27, no. 7-8, pp. 701–708, 2014.
View at: Publisher Site | Google Scholar
A. Bustamante, C. Dominguez, V. Rodriguez-Sureda et al., “Prognostic value of plasma chitotriosidase activity in acute stroke patients,” International Journal of Stroke, vol. 9, no. 7, pp. 910–916, 2014.
View at: Publisher Site | Google Scholar
B. S. Yildiz, B. Barutcuoglu, Y. I. Alihanoglu et al., “Serum chitotriosidase activity in acute coronary syndrome,” Journal of Atherosclerosis and Thrombosis, vol. 20, no. 2, pp. 134–141, 2013.
View at: Publisher Site | Google Scholar
M. R. Safarinejad and S. Safarinejad, “Plasma chitotriosidase activity and arteriogenic erectile dysfunction: association with the presence, severity, and duration,” The Journal of Sexual Medicine, 2010.
View at: Publisher Site | Google Scholar
V. Pagliardini, S. Pagliardini, L. Corrado et al., “Chitotriosidase and lysosomal enzymes as potential biomarkers of disease progression in amyotrophic lateral sclerosis: a survey clinic-based study,” Journal of the Neurological Sciences, vol. 348, no. 1-2, pp. 245–250, 2015.
View at: Publisher Site | Google Scholar
B. Olsson, C. Malmeström, H. Basun et al., “Extreme stability of chitotriosidase in cerebrospinal fluid makes it a suitable marker for microglial activation in clinical trials,” Journal of Alzheimer's Disease, vol. 32, no. 2, pp. 273–276, 2012.
View at: Publisher Site | Google Scholar
P. J. Orchard, T. Lund, W. Miller et al., “Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy,” Journal of Neuroinflammation, vol. 8, article 144, 2011.
View at: Publisher Site | Google Scholar
A. Aydogdu, I. Tasci, S. Tapan et al., “Women with polycystic ovary syndrome have increased plasma chitotriosidase activity: a pathophysiological link between inflammation and impaired insulin sensitivity?” Experimental and Clinical Endocrinology and Diabetes, vol. 120, no. 5, pp. 261–265, 2012.
View at: Publisher Site | Google Scholar
I. Alanbay, H. Coksuer, C. M. Ercan et al., “Chitotriosidase levels in patients with severe endometriosis,” Gynecological Endocrinology, vol. 28, no. 3, pp. 220–223, 2012.
View at: Publisher Site | Google Scholar
Ü. Aksoy, H. Aksoy, G. Açmaz, M. Babayiğit, and Ö. Kandemir, “Umbilical artery serum chitotriosidase concentration in pregnancies complicated by preeclampsia and relationship between chitotriosidase levels and fetal blood flow velocity,” Hypertension in Pregnancy, vol. 32, no. 4, pp. 401–409, 2013.
View at: Publisher Site | Google Scholar
A. Taylan, O. Gurler, B. Toprak et al., “S1000A12, chitotriosidase, and resolvin D1 as potential biomarkers of familial mediterranean fever,” Journal of Korean Medical Science, vol. 30, no. 9, pp. 1241–1245, 2015.
View at: Publisher Site | Google Scholar
R. Barone, G. Bertrand, J. Simporè, M. Malaguarnera, and S. Musumeci, “Plasma chitotriosidase activity in β-thalassemia major: a comparative study between Sicilian and Sardinian patients,” Clinica Chimica Acta, vol. 306, no. 1-2, pp. 91–96, 2001.
View at: Publisher Site | Google Scholar
A. Acar, M. Keskek, F. K. Işman, M. Kucur, and M. Tez, “Serum chitotriosidase activity in acute appendicitis: preliminary results,” American Journal of Emergency Medicine, vol. 30, no. 5, pp. 775–777, 2012.
View at: Publisher Site | Google Scholar
J. K. H. Brunner, S. Scholl-Bürgi, D. Hössinger, P. Wondrak, M. Prelog, and L.-B. Zimmerhackl, “Chitotriosidase activity in juvenile idiopathic arthritis,” Rheumatology International, vol. 28, no. 9, pp. 949–950, 2008.
View at: Publisher Site | Google Scholar
M. Kucur, F. K. Isman, C. Balci et al., “Serum YKL-40 levels and chitotriosidase activity as potential biomarkers in primary prostate cancer and benign prostatic hyperplasia,” Urologic Oncology: Seminars and Original Investigations, vol. 26, no. 1, pp. 47–52, 2008.
View at: Publisher Site | Google Scholar

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Copyright © 2016 Mohamed A. Elmonem et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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