Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143, USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 11/2008; 122(5):944-950.e3. DOI: 10.1016/j.jaci.2008.08.023
Source: PubMed


Chitinolytic enzymes play important roles in the pathophysiology of allergic airway responses in mouse models of asthma. Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) have chitinolytic activity, but relatively little is known about their expression in human asthma.
We sought to determine the expression and activity of AMCase and CHIT1 in healthy subjects, subjects with asthma, and habitual smokers, taking account of the null 24-bp duplication in the CHIT1 gene.
We measured chitinase activity in bronchoalveolar lavage (BAL) fluid at multiple pHs by using a synthetic chitin substrate. We also determined AMCase and CHIT1 gene expression in epithelial brushings and BAL fluid macrophages by means of real time RT-PCR. Paired DNA samples were genotyped for the CHIT1 duplication.
In all subgroups the pH profile of chitinase activity in BAL fluid matched that of CHIT1, but not AMCase, and chitinase activity was absent in subjects genetically deficient in active CHIT1. Although AMCase protein was detectable in lavage fluid, AMCase transcripts in macrophages were consistent with an isoform lacking enzymatic activity. Median chitinase activity in BAL fluid tended to be lower than normal in asthmatic subjects but was increased 7-fold in habitual smokers, where CHIT1 gene expression in macrophages was increased.
Chitinase activity in the lung is the result of CHIT1 activity. Although AMCase protein is detectable in the lung, our data indicate that it is inactive. Chitinase activity is not increased in subjects with asthma and in fact tends to be decreased. The high levels of chitinase activity in habitual smokers result from upregulation of CHIT1 gene expression, especially in macrophages.

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Available from: Samantha Donnelly, Jul 15, 2014
    • "Chitinase 1 (CHIT1), also known as chitotriosidase, was the first active chitinase to be discovered in humans (Boot et al. 1995). The CHIT1 gene is expressed in various tissues and CHIT1 is the main functional chitinase in the human lung (Seibold et al. 2008). The expression is primarily derived from activated macrophages and neutrophils (Boot et al. 1995; Boussac and Garin 2000; Malaguarnera et al. 2006). "
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    ABSTRACT: Chitin is a vital polysaccharide component of protective structures in many eukaryotic organisms, but seems absent in vertebrates. Chitin or chitin oligomers are therefore prime candidates for non-self molecules, which are recognized and degraded by the vertebrate immune system. Despite the absence of polymeric chitin in vertebrates chitinases and chitinase like proteins are well conserved in vertebrate species. In many studies these proteins have been found to be involved in immune regulation and in mediating the degradation of chitinous external protective structures of invading pathogens. Several important aspects of chitin immunostimulation have recently been uncovered, advancing our understanding of the complex regulatory mechanisms that chitin mediates. Likewise, the last few years have seen large advances in our understanding of the mechanisms and molecular interactions of chitinases and chitinase like proteins in relation to immune response regulation. It is becoming increasingly clear that their function in this context is not exclusive to chitin producing pathogens, but includes bacterial infections and cancer signaling as well. Here we provide an overview of the immune signaling properties of chitin and other closely related biomolecules. We also review the latest literature on chitinases and chitinase like proteins of the GH18 family. Finally, we examine the existing literature on zebrafish chitinases, and propose the use of zebrafish as a versatile model to complement the existing murine models. This could especially be of benefit to the exploration of the function of chitinases in infectious diseases using high throughput approaches and pharmaceutical interventions. © The Author 2015. Published by Oxford University Press.
    No preview · Article · Jan 2015 · Glycobiology
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    • "It is highly expressed by activated macrophages (Van Eijk et al., 2005) and is pre-formed in granules of neutrophils (Boussac & Garin, 2000). At the tissue level, CHIT1 is expressed in the human lung (Seibold et al., 2008), human lachrymal glands (Hall, Morroll, Tighe, Götz, & Falcone, 2008) and in both bone marrow and spleen of mice (Boot et al., 2005). "
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    ABSTRACT: The human genome encodes a gene for an enzymatically active chitinase (CHIT1) located in a single copy on Chromosome 1, which is highly expressed by activated macrophages and in other cells of the innate immune response. Several dysfunctional mutations are known in CHIT1, including a 24-bp duplication in Exon 10 causing catalytic deficiency. This duplication is a common variant conserved in many human populations, except in West and South Africans. Thus it has been proposed that human migration out of Africa and the consequent reduction of exposure to chitin from environmental factors may have enabled the conservation of dysfunctional mutations in human chitinases. Our data obtained from 85 indigenous Amerindians from Peru, representative of populations characterized by high prevalence of chitin-bearing enteroparasites and intense entomophagy, reveal a very high frequency of the 24-bp duplication (47.06%), and of other single nucleotide polymorphisms which are known to partially affect enzymatic activity (G102S: 42.7% and A442G/V: 25.5%). Our finding is in line with a founder effect, but appears to confute our previous hypothesis of a protective role against parasite infection and sustains the discussion on the redundancy of chitinolytic function.
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    • "Mammals are known to produce two types of chitinases: chitotriosidase and acidic mammalian chitinase (AMCase) [9]. Chitotriosidase is produced by macrophages and polymorphonuclear neutrophils [10], [11] and can be found in the lungs of mammals [12], [13] as well as in lacrimal glands [14]. AMCase is an exochitinase produced by macrophages and epithelial cells [15] and is found mainly in the gastro-intestinal tract of mammals to digest nutritional chitin, though it was also found in the lung at low concentrations [10]. "
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