Abstract
The role of chitinases has been focused as potential biomarkers in a wide number of inflammatory diseases, in monitoring active disease state, and predicting prognosis and response to therapies. The main chitinases, CHIT1 and YKL-40, are derived from 18 glycosyl hydrolases macrophage activation and play important roles in defense against chitin-containing pathogens and in food processing. Moreover, chitinases may have organ- as well as cell-specific effects in the context of infectious diseases and inflammatory disorders and able to induce tissue remodelling. The CHIT1 measurement is an easy, reproducible, reliable, and cost-effective affordable assay. The clinical use of CHIT1 for the screening of lysosomal storage disorders is quite practical, when proper cut-off values are determined for each laboratory. The potential of CHIT1 and chitinases has not been fully explored yet and future studies will produce many surprising discoveries in the immunology and allergology fields of research. However, since the presence of a null CHIT1 gene in a subpopulation would be responsible of false-negative values, the assay should be completed with the other markers such ACE and, if necessary, by genetic analysis when CHIT1 is unexpected low.
Functions and role of chitinases
This review has been developed by searching in the PubMed database literature from 2000 until July 2022 using the search terms “chitinase” or “chitotriosidase” and/or “immune-mediate and/or biomarker”. Only articles published in English were reviewed. Both articles dealing with chitinases in crops/plants or showing human population studies with low statistical power were excluded. The final reference list was obtained mainly based on originality and relevance to the topic of the review.
Chitinases are omnipresent throughout nature and are produced by a wide range of organisms from bacteria to higher plants and animals in which they play important roles [1], [2], [3] (Figure 1). These enzymes are responsible for the biological degradation of chitin, an essential structural component of different fungi, nematodes, arthropods, insects, and crustaceans. Chitin is composed of linear β-1,4-linked N-acetylglucosamine (NAG) units forming chains that are packed into crystals with intervening amorphous regions. Chitinases participate in nutrition, parasitism, morphogenesis and immunity. Many organisms, produce also inactive chitinase-like lectins lacking enzymatic activity and involved in several regulatory functions [4].
![Figure 1:
Mechanism of chitin hydrolysis by family 18 glycosyl hydrolases. Figure reprinted from MacDonald et al. [13], with permission from Wiley. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.](/document/doi/10.1515/cclm-2022-0767/asset/graphic/j_cclm-2022-0767_fig_001.jpg)
Mechanism of chitin hydrolysis by family 18 glycosyl hydrolases. Figure reprinted from MacDonald et al. [13], with permission from Wiley. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chitinases appear to be key regulators of medium-size chitin fragments production responsible for immunomodulation switching on the same chitinases; they would also help to limit local injury by fostering the more complete degradation of chitin.
Based on sequence homologies, chitinases fall into two groups: families 18 and 19 of glycosyl hydrolases [5]. Members of family 18 employ a substrate-assisted reaction mechanism [6, 7], whereas those of family 19 adopt a lysozyme-like fold-and-reaction mechanism [8], suggesting an independent evolution of these families.
18 Glycosyl hydroxylases are a class of ancient, conserved evolutionary enzymes [5] whose size range from 20 kDa to about 90 kDa [9]. They were isolated from the stomachs of certain mammals, including humans [10] but enzyme activity can be detected in human blood [11] and cartilage [12].
The generally accepted mechanism of action of family 18 involves neighboring group participation (substrate-assisted reaction mechanism [6, 7]) with the formation of an oxazolinium intermediate within the one subsite (Figure 1, from MacDonald et al. [13]). Inhibitors of chitinases mimicking the oxazolinium intermediate moiety [7, 14], have several potential applications, including use as insecticides and fungicides [15], the prevention of human malaria-parasite transmission [16], and the treatment of human asthma [17] as well as the sexually transmitted disease human trichomoniasis [18].
As the main component of the fungal cell wall and insect shell playing an important role in resisting crop diseases and insect pests, chitin is the ideal target of chitinase when the latter is used as an antifungal agent [19].
Human chitotriosidases
Although humans do not synthesize chitin of their own, their genome expresses certain chitinases whose physiological role has been attracting the interest of researchers [20, 21] even in the biotechnology area of research [22] (Figure 2).
Chitinases proposed functions in organisms.
Human chitotriosidase (CHIT1) is a glycosyl hydrolase belonging to the family of chitinases. It is expressed in macrophages at very low levels in healthy persons [23] but is highly expressed in activated macrophages and different monocyte-derived cell lines such as Kupffer cells and osteoclasts. A striking increase of plasma CHIT1 activity is observed in serum from Gaucher’s disease (GD) type I patients, and in many other inherited and acquired conditions, sharing macrophage activation [24, 25].
CHIT1 and acidic mammalian chitinase (AMCase) [25, 26] along with several chitinase-like proteins (CLPs) have been described. While bacteria degrade chitin for energy supply, human chitinases play a protective role against chitin-containing pathogens through their capability to degrade chitin present in the cell wall of pathogens; therefore, human chitinases are considered parts of the innate immune system possibly through activation of signaling pathways involved in inflammation [27, 28].
The recombinant CHIT1 inhibits the hyphal growth of fungi [29]. Elevated CHIT1 is associated with several potent growth factors able to induce tissue remodeling [reviewed in 30]. Furthermore, atherosclerotic plaque formation and subsequent thrombosis were enhanced by CHIT1 produced by macrophages [31, 32]. All together these lines of evidence suggest that CHIT1 may have organ- as well as cell-specific effects in the context of infectious diseases and inflammatory disorders.
An ancient gene duplication event likely occurred very early in tetrapod evolution and led to the specialization of two active chitinases, CHIT1 and AMCase (Figure 3). Then, more recent duplications followed by loss-of-enzymatic-function mutations, led to the subsequent evolution of chi-lectins (ChiLs) [33, 34] and CLPs molecules which lack enzymatic activity but can bind to chitin or chitooligosaccharides (e.g. the structurally related chitinase-like protein YKL-40) [4, 35]. Both these hydrolases, the “true-chitinases” CHIT1/AMCase [36, 37] and the “chitinase like protein” YKL-40 [38], are being evaluated as chemical mediators or biomarkers involved in inflammation-mediated diseases.
Chitinase classification. CLP, chitinase-like proteins; ChiLs, chi-lectins; CHI3L1, CHI3L2, chitinase-3-like 1, like 2; OVGP1, oviductin; SI-CLP, stabilin-1 interacting chitinase-like protein or CHID; AMCase, acidic mammalian chitinase (red arrows indicate proposed evolutionary events in the chitinase protein family).
Chitin and the immune system
The immune system is a complex machinery involving many cells and cytokines able to produce an orchestrated response of the organism to non-self-antigens [39] (Figure 4).
A simplified overview of the main cells mediated pathways set in motion in the adaptive immune response.
On the other side, the immune response needs to be finely controlled as it is an energy costly process that results also in damage to the host tissue. Therefore, a complete and rapid resolution of the immune response is an important part of its global efficacy. There is a range of immune cells including Tregs, express anti-inflammatory actions by IL-10 expression to suppress inflammatory process [40].
Amongst the substances with immunomodulatory effects, there is chitin, first identified in 1811 by the French scientist Henri Braconnot, who discovered an alkali resistant fraction during his studies of fungi. It is the polysaccharide most abundant in nature after cellulose, and it represents a structural component in the cell walls of fungi, in the exoskeleton of crustaceans [41], insects [42], and eggshells of nematodes [43]. Interestingly, chitin is also a common component of allergy-triggering antigens including those in shrimp, crab, cockroaches, and house dust mites [44], [45], [46]. Chitin and chitosan (a chitin deacetylated derivative) are potential targets for recognition by the mammalian immune system since mammalians lack such biopolymers naturally. Chitin is sensed primarily in the lungs or gut where it activates a variety of innate (eosinophils, macrophages) and adaptive immune cells (IL-4/IL-13 expressing T helper type-2 lymphocytes) [47]. Chitin induces cytokine production, leukocyte recruitment, and alternative macrophage activation [48]. The chitin-mediated response is size-dependent: only small chitin fragments of 40- to 70-μm size – but not large size chitin polymers such as those of chitin-containing pathogens that are biologically inert – can be sensed as “non-self” by the innate immune system. These chitin fragments have immunomodulatory effects, including the ability to recruit and activate innate immune cells and induce cytokine and chemokine production via a variety of cell surface receptors including macrophage mannose receptor, toll-like receptor 2 (TLR-2), and Dectin-1 [reviewed in 27].
Lee et al. [49] hypothesize that when chitin-containing pathogens (with inert large chitin polymers) enter a host, they trigger the innate anti-pathogen response mediated by oxidants and chitinases that in turn generate additional chitin proinflammatory 40–70 μm-size fragments. The latter serve as an “alarm signal” to induce and amplify local inflammation by activating pattern recognition receptors and pathways like NF-κB. These medium-size chitin fragments also regulate the intensity and chronicity of local inflammation by regulating local inflammatory cell apoptosis. The immune response machinery would be in motion to deal with the pathogen until smaller chitin fragments (<40 μm) would be generated by chitinases; these smaller chitin fragments appear able to induce molecules such as IL-10, able to control the local inflammatory response as a feedback mechanism.
In this hypothesis chitin degradation to different fragments size would initially maintain switched on immunomodulation and then triggers the end of it (Figure 5).
Roles of chitinases in response to chitin-bearing organisms (fungi, nematodes, crabs, cockroaches, shrimps, dermatophagoides) indicating that an efficacious complete immune response should involve control of the possible cellular and tissue damage caused by a maintained inflammatory process. Chitin degradation to different fragments size (blue hexagons: chitin monomers) would initially maintain switched on immunomodulation and then triggers the end of it through IL-10 release (see the text).
The chitinase activity assays
The chitinase CHIT1 activity assay in biological samples is relatively simple. A non-fluorescent substrate is cleaved by enzymatically active chitinase to produce a fluorescent product, which is then measured as an indirect marker of chitinase activity. The chitinases within the samples break down the substrate 4-methylumbelliferyl-d-N,N′-diacetylchitobiose present in the 1× McIlvain buffer. A fluorescent molecule 4-methylumbelliferyl is released. By measuring the total fluorescence of each well, an accurate measurement of the active chitinase in each sample can be obtained. Because the breakdown of chitin by CHIT1 is a hydrolytic reaction, the stop buffer, a mixture of 0.3 M glycine and NaOH (12.0 g/L at pH 10.6), ends the breakdown of chitin by creating an environment that is too basic for the enzyme to function [50].
Plasma analysis of YKL-40 is performed on EDTA-blood samples left on the blood cells at room temperature for less than 8 h because it is known that in EDTA plasma YKL-40 is only stable when samples are processed within this time. Then, the samples can be separated by centrifugation at 2000g for 10 min at room temperature and plasma EDTA samples stored in aliquots at −80 °C until analysis. Plasma levels of YKL-40 are determined in duplicates by a commercial two-site, sandwich-type enzyme-linked immunosorbent assay (Quidel, Santa Clara, CA, USA) using streptavidin coated microplate wells, a biotinylated- Fab monoclonal capture antibody, and an alkaline phosphatase-labeled polyclonal detection antibody. The detection limit is 20 μg/L. The intra-assay coefficient of variation (CV) is ≤ 5.0% and inter-assay CVs ≤ 10.2%. The samples are analyzed blinded to clinical parameters and study endpoint [51].
The chitinases as a potential markers of inflammation-mediated diseases
CHIT1 and YKL-40, are significantly higher in patients with certain bioimplants and these markers of monocyte/macrophage activation rose progressively as adverse reactions progress [52].
CHIT1 usability as a screening marker is limited by the evidence that the enzyme is a nonspecific marker of macrophage activation and is deficient in about 6–21% of Caucasians due to homozygosity of 24-bp duplication mutation at exon 10 of the CHIT1 gene [53]. However, in non-deficient patients with an established diagnosis, CHIT1 has shown to be of great utility to monitor compliance and response to treatment especially when there is the involvement of inflammatory pathways [54, 55].
YKL-40 has a substantial role in acute and chronic infections and in cancer, where it is associated with a poor prognosis. Indeed, YKL-40 plays a role in relation to cell migration, reorganization and tissue remodelling during atherogenesis and seems to play a pivotal role in the differentiation of monocytes to activated macrophages in tissues characterized by inflammation. Together these data imply a significant role of YKL-40 in endothelial dysfunction and in the process of atherosclerosis [56].
Modic vertebral endplate changes (MC) represent an intense inflammatory status where CHI3L2 is found as marker of activation of host defense response and immunological pathways [57].
The chitinases in lysosomal storage diseases
CHIT1 has been demonstrated as an established or a candidate screening marker, severity marker, and/or therapeutic monitor for lysosomal storage diseases (LSDs) which are a group of 70 monogenic disorders caused by mutations in genes encoding lysosomal proteins, such as glycosidases, proteases, integral membrane proteins, transporters, enzyme modifiers, or activators. The consequence is a progressive accumulation of metabolic products inside lysosomes that ultimately leads to cell dysfunction and death [58] (Table 1).
Simplified list of the main LSD, the enzyme deficiency causing them, the accumulated material and the main clinical features observed.
| Disease | Accumulated material | Enzyme deficiency | Heredity | Special features |
|---|---|---|---|---|
| Gaucher | Glucorebroside | Glucorebrosidase | RAa | Adult form: increased phosphatase acid, pathological fractures. |
| Niemann-Pick | Sphingomyelin | Sphingomyelinase | RAa | Pulmonary infiltrations, skin brownish, neuropathic form of childhood, blue-sea histocytes. |
| Metachromatic leukodystrophy | Galactocerebroside | Galactocerebrosidase | RAa | Increase in protein, early anomalies of the limb in walking childhood; peripheral neuropathy. |
| Fabry | Globotriaosylceramide | Alpha-galactosidase A | X-linked | Angiokeratoma, thrombosis, hypohidrosis |
| Fucosidosis | Fucose-containing glyolipids | Alpha-fucosidase | RAa | Coarse facies, increase in electrolytes of sweat, angiokeratoma in young people. |
| Farber | Ceramide | Ceramidase | RAa | Arthropathy, subcutaneous periarticular and visceral nodules (lipogranulomatosis) |
| Gangliosidosis Generalized | Ganglioside GM1 | Beta-galactosidase | RAa | Coarse facies, macroglossia mucopolysacchariduria; blindness in infancy |
| Tay-Sachs | Ganglioside GM2 | Hexosaminidase A | RAa | Macrocephaly, hyperacusis in infancy |
| Sandhoff | Ganglioside GM2 | Hexosaminidase A/B | RAa | Macrocephaly, hyperacusis, visceral histiocytosis |
-
aRA, recessive autosomal; LSD, lysosomal storage disease.
CHIT1 is of clinical utility for both screening and monitoring the efficacy of therapy and severity in Gaucher Disease (GD) or β-glucocerebrosidase deficiency [59] and insphingolipidoses, such as Niemann Pick [60], GM1-gangliosidosis, and Krabbe’s disease [61], [62], [63]. The use by CHIT1 as biomarker could investigate the progression of disease from GD to monoclonal gammopathy and to multiple myeloma [64, 65].
Fabry disease is an important an X-linked LSD caused by the deficiency of the lysosomal enzyme α-galactosidase A (AGA), resulting in glycosphingolipids accumulation in lysosomes of several cell types, as endothelial cells and podocytes [66]. Unlike of GD where CHIT1 has proven an extremely useful biomarker of pathophysiological processes in this disorder [67], in Fabry disease patients, lipid-laden macrophages seem to play a far less prominent role in the pathogenesis of the disease and consequently the value of plasma CHIT1 appears more limited for this condition [68].
CHIT1 represents a promising clinical biomarker and therapeutic monitor also for nephropathic cystinosis (NC). There are many lines of evidence that macrophages are activated by different types of crystals; cystine crystals have been observed in tissue macrophages of cystinotic patients [69]. Plasma CHIT1 activity was significantly elevated in cystinotic patients at diagnosis over age; it matched normal and renal controls and correlated with white blood cells (WBC) cystine assay [70] for treated patients above 2 years of age. Moreover, bone marrow cell transplantation [71] and hematopoietic stem cell gene therapy [72], are both lines of intervention proven successful in human NC patients. CHIT1 activity measurements represent a rapid and non-invasive method for routine follow-up of patient’s response post-transplantation compared to the invasive estimation of cystine accumulation in tissue biopsies and cystine measuring in the donor’s WBCs.
Plasma CHIT1 activity was increased in Krabbe disease patients where it ranged from 1.4 to 10.4 times the upper normal limit [73]. Krabbe disease is caused by the deficiency of β-galactocerebrosidase (GALC, E.C. 3.2.146) which impairs the degradation of galactocerebroside, a major myelin lipid, and of galactosylsphingosine or psychosine [74, 75], resulting in the formation of the characteristic multinucleated macrophages known as globoid cells. CHIT1 increased activity observed in Krabbe disease patients could reflect the psychosine-induced activation of peripheral immune cells [76, 77], strongly suggesting that assaying this enzyme activity is in the diagnosis/monitoring of Krabbe disease [61, 78].
CHIT1 activity was proposed as an useful biomarker in the screening of other LSDs such as Farber disease (FD), GM1 gangliosidosis, and Sialidosis type II [79]. Acid ceramidase deficiency in FD produces accumulation of ceramide resulting in the clinical manifestations. However, it could not be ruled out that elevation of CHIT1 in a FD patient could be secondary to intercurrent infection rather than a direct expression of the disease itself [80].
The genetic deficiency of the lysosomal enzyme β-galactosidase involved in the degradation of glycoproteins, glycolipids, and keratan sulfate cause the GM1 gangliosidosis, a neurodegenerative disorder where CHIT1 shows a tenfold greater enzyme activity in the infantile form compared to the late-infantile form [81].
Eventually, the deficiency of alpha-N-acetyl neuraminidase-1 (NEU1) is the cause of sialidosis. Increased plasma CHIT1 was observed only in the infantile form of the disease but not in the congenital form, suggesting that enzyme activity could be a supplementary biochemical marker that might be worth investigating in such patients [81].
The chitinases in infectious and parasitic diseases
There are many lines of evidence that CHIT1 or YKL-40 are useful markers for prognosis and therapeutic monitoring in different infectious diseases such as systemic fungal infections, tuberculosis, leprosy [34, 82] and malaria [83] (Table 2).
Chitinases and infectious and parasitic diseases. COPD, chronic obstructive pulmonary bronchitis disease.
| Disease | Aetiology | Clinical features | Prognosis | References |
|---|---|---|---|---|
| Necrotizing soft-tissue infection | Fast Bacterial infection | Necrosis of soft tissues | YKL-40 predictor of 30-day mortality | [82] |
| Fungal | C. Albicans | Cystic fibrosis (CF)-associated lung disease | CHIT1 raises efficient antifungal defence against systemic candidiasis | [84, 85] |
| Fungal | Aspergillus | Bronchiectasis COPD | Systemic CHIT1 activity related to disease exacerbation phenotype in South-East Asian patients | [86] |
| Leprosy (Hansen’s disease) | Mycobacterium leprae | Nerves, skin, eyes, and lining of the nose involvement | CHIT1 activity correlated with levels of neopterin; CHIT1 distinguishes multibacillary from paucibacillary leprosy |
[87] |
| Crimean-Congo fever (CCHF) | Virus of the genus Nairovirus that is endemic in Africa, Asia (particularly in the Middle East), and southeast Europe | Hemorrhagic fever | Low CHIT1 activity may be a poor prognostic marker : median CHIT1 activity was higher in the non-fatal CCHF group compared with the fatal CCHF group | [88] |
| Filariasis (elephantiasis) | Mosquitoes which carry on filarial parasites | Obstruction of the lymphatic system | A polymorphism in the human CHIT1 gene was associated with susceptibility to filarial infection in a filarial-endemic region of South India | [89] |
| Brucellosis | Brucella abortus | Zoonotic infection with musculoskeletal involvement | Neopterin and are high and decrease with therapy | [90] |
| Scrub typhus | Rickettsia genus | Systemic endothelitis | High YKL-40 correlates with disease severity | [91] |
| Schistosomiasis | Schistosoma haematobium | Chronic bladder and lung inflammation | Serum YKL-40 levels differed between infected and uninfected people before and after treatment | [92] |
| Toxoplasmosis | Toxoplasma gondii | Systemic inflammation | YKL-40 correlates with disease stage (p<0.001) | [93] |
Mammalian chitinases are linked to airway infections, particularly fungal, where they are considered a key innate immune defense mechanism to pulmonary infection with Cryptococcus, Aspergillus, and Candida [84, 85].
Take home messages: proposed biomarker roles for chitinases in different human diseases.
| Chitinase biomarker | Disease group | Disease | Biological sample | References |
|---|---|---|---|---|
| Screening | LSD | GD; Niemann Pick; Krabbe; Farber; GM1; Sialidosis type II | Plasma/serum | [54, 55, 59], [60], [61], [62, 67, 73, 78], [79], [80], [81] |
| Infectious diseases | Filariasis, CF | Plasma/serum | [84, 89] | |
| Respiratory diseases | Interstitial diseases, COPD, Bronchiectasis. | Plasma/serum | [86] | |
| Neurological diseases | ALS, NMO, MS | CSF | [123] | |
| Miscellaneous | FMF; acute appendicitis; JIA; sarcoidosis. | Plasma/serum/BAL | [156, 162] | |
| Therapeutic monitoring | LSD | Cystinosis, Fabry | Plasma/serum | [55, 68, 69] |
| Infectious diseases | Systemic fungal infections; tuberculosis; brucellosis; leprosy. | Plasma/serum | [87, 90] | |
| Miscellaneous | β-thalassemia; Sarcoidosis; Lichen planus; Psoriasis | Plasma/serum | [153, 154, 171, 178] | |
| Marker of severity | LSD | Krabbe | Plasma/serum | [61, 62] |
| Respiratory diseases | Asthma; COPD | Plasma/serum BAL (in COPD) |
[95, 96] | |
| Cardiovascular diseases | Atherosclerosis; Erectile disfunction | Plasma/serum | [91, 92, 107] | |
| Neurological diseases | ALS | Plasma/serum; CSF | [122, 123] | |
| Miscellaneous | NAFLD; FMF; β-thalassemia; JIA; endometriosis; preeclampsia; Sweet’s syndrome | Plasma/serum | [106, 116, 151, 153, 176] | |
| Prognosis | Infectious diseases | Systemic fungal infections; malaria; tuberculosis; Leprosy; CCHF. | Plasma/serum | [87], [88], [89] |
| Cardiovascular diseases | Stroke; Coronary artery disease | Plasma/serum | [103, 119] | |
| Neurological diseases | MS | CSF | [125] | |
| Gynecological and obstetrical diseases | PCOS | Plasma/serum | [143] | |
| Miscellaneous | Prostate cancer; Sarcoidosis | Plasma/serum/BAL | [55, 164] | |
| Marker of endothelial damage/nephropathy progression | Endocrinological diseases | Diabetes | Plasma/serum | [92, 106] |
-
AML, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary bronchitis disease; LSD, lysosomal storage diseases; FMF, familial mediterranean fever; GD, gaucher disease; MS, multiple sclerosis; NAFLD, non-alcoholic fatty liver disease; NMO, neuromyelitis optica; JIA, juvenile idiopathic arthritis; PCOS, polycystic ovary syndrome.
In bronchiectasis patients, monitoring CHIT1 activity may improve risk stratification in appropriate bronchiectasis cohorts and allow better identification of those at high risk for fungal-associated consequences, which include disease exacerbations [86].
In Leprosy (Hansen’s disease), CHIT1 activity was potentially useful in distinguishing multibacillary from paucibacillary leprosy and in monitoring response to corticosteroid therapy in erythema nodosum leprosum patients. CHIT1 activity correlated with levels of neopterin, another macrophage activation marker [87].
In Crimean-Congo hemorrhagic fever (CCHF) patients, relatively low CHIT1 enzyme activities may be a poor prognostic marker [88].
In lymphatic filariasis, CHIT1 was proposed to represent a marker in the screening of this disease. A polymorphism in the human CHIT1 gene, which is highly expressed in phagocytic cells, was associated with susceptibility to filarial infection in a filarial-endemic region of South India. The evidence that the microfilarial sheath of filarial parasite contains chitin may explain the role of CHIT1 in modulating the immune response against complex pathogens, such as the filarial parasite [89].
In brucellosis serum neopterin and CHIT1 appeared high and decreased with therapy; further, of the two markers analyzed, CHIT1 seemed to be more valuable in reflecting the response of brucellosis patients to treatment [90].
Scrub typhus is characterized by elevated levels of monocyte/macrophage and endothelial related inflammatory markers among which YKL-40 may contribute to disease severity and clinical outcome [91].
In Schistosoma haematobium infected children, serum YKL-40 levels differed between infected and uninfected people before and after anti-helminthic treatment. The greatest difference occurred in the youngest age group, in keeping with the period when schistosome-related pathological processes were initiated [92].
In toxoplasmosis YKL-40 is unique and sophisticated biomarker able to detect the stage of the disease, whether acute or chronic (p<0.001), besides its ability to detect the infection [93].
The chitinases in respiratory diseases
Allergen exposure leads to asthma through the development of IgE-mediated airways inflammation, bronchial hyperresponsiveness, and reversible airflow obstruction [94], whereas COPD is a debilitating respiratory condition characterized by chronic airway inflammation and emphysematous alveolar destruction, with an abnormal inflammatory response able to produce lung injury.
CHIT1 and YKL-40, were higher in subjects with chronic obstructive pulmonary disease (COPD) than in patients with mild to moderate asthma or those with severe asthma [95, 96]. In allergic nasal polyps, the increased chitinolytic activities of AMCase and CHIT1 confirms the pathogenesis of the disease, suggesting inhibition of chitinolytic activity as a potential novel therapeutic strategy [97].
The increased chitinases levels correlated with reduced lung function and were relatively steroid-refractory biomarkers [98].
Therefore, CHIT1 can assess severe, chronic inflammation rather than acute lung inflammation.
Strategies aimed at specifically neutralizing chitinolytic activity or at limiting CHIT1 synthesis can be of therapeutic value to improve COPD management [96]. Chitinases can be monitored as biomarkers of decline in lung function in patients with asthma, COPD, fibrosis, infections, or pediatric conditions such as bronchopulmonary dysplasia [98]. There is a relationship between serum level of both YKL-40 and CHIT1 and age in patients with obstructive airway diseases (asthma and COPD) and healthy individuals [99].
CHIT1 may represent a potential biomarker for resistance to obstructive, COPD-like lung injury, as shown in a case-control study involving firefighters from the 9/11 World Trade Center disaster. The enzyme levels were also associated with recovery of lung function, whereas the elevated IgE was the risk factor for airflow obstruction and progressive lung function decline [100, 101].
In lung autoimmune diseases as interstitial lung disease (ILD), scleroderma, or systemic sclerosis (SSc) CHIT1 is a potential biomarker for lung fibrosis [102]. Patients with ILD showed high levels of circulating CHIT1 activity that correlates with disease severity; furthermore, CHIT1 plays a critical role in the pathogenesis of SSc-relevant tissue fibrotic responses or to have modulating capacity of TGF-β1 signalling, acting as a biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis [103, 104].
The chitinases in endocrinological diseases
Serum CHIT1 activity increases in patients with newly diagnosed, untreated, and uncomplicated type-2 diabetes mellitus (T2DM), a major cause of accelerated atherosclerosis [105].
Extracts of atherosclerotic tissue showed an increase in CHIT1 activity up to 55-fold, demonstrating a clear association between CHIT1 expression and lipid-laden macrophages in the atherosclerotic vessel wall [106].
In diabetic complications, CHIT1 enzyme activity correlated positively with the progression of nephropathy [107]. Other studies showed that in both type 1 and 2 diabetes mellitus, CHIT1 activity was correlated with age, glomerular filtration rate, and urine albumin to creatinine ratio [106], [107], [108]. In a recent study, the enzymatic activity of CHIT1 correlated with neuropathy and retinopathy in type 1 diabetes mellitus. Moreover, CHIT1 activity was higher than those of the controls and related to glycosylated hemoglobin HbA1c levels [109].
An interesting difference was reported between non-smokers and smokers, the latter showing higher enzyme activity likely due to the persistent inflammatory response generated by smoking [110].
The chitinases in cardiovascular diseases
CHIT1 level represents a marker of macrophage activity in atherosclerotic plaque [32] and related to the width and severity of atherosclerotic lesions [111] and pre-stroke infections [112]. Furthermore, plasma CHIT1 activity significantly correlated with intima-media thickness (IMT) [113] and was higher in patients with stroke and ischemic heart disease compared to healthy controls [114]. Kologlu et al. [115] reported that CHIT1 level was more effective in predicting atherosclerosis in dyslipidemic children compared to hs-CRP, IL-6, and TNF-α. Further, serum CHIT1 activity was a strong marker of coronary artery disease [116]. CHIT1 level was increased in a heterogeneous group of atherothrombotic patients with atherothrombotic stroke or with unstable angina pectoris; moreover, CHIT1 predicts the risk of new cardiovascular events in the following four years, independently from CRP [114]. Güçlü et al. [117] reported a correlation between serum CHIT1 level and carotid IMT in hemodialysis patients, hypothesizing a possible role for CHIT1 in the development of atherosclerosis during uremia.
An increased risk of atherosclerosis is observed in sarcoidosis patients, irrespective of exposure to steroids [118].
The role played by CHIT1 as a marker of prognosis in stroke patients is likely due to the evidence that its activity represents a sensitive parameter of activated macrophage proliferation and therefore reflects the innate inflammatory response that occurs after brain ischemia [119].
Among initially healthy U.S. women, plasma levels of the proinflammatory CLPs, YKL-40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke; YKL-40 levels were higher in women with hypertension, diabetes, and obesity and was significantly associated with incident thromboembolic stroke (p=0.006) [120].
The chitinases in neurological diseases
Amyotrophic lateral sclerosis (ALS) is determined by the loss of spinal, bulbar, and cortical motor neurons, which leads to paralysis of voluntary muscles involving also respiratory muscles. There are different reports of substantially elevated CHIT1 expression and activity in the cerebrospinal, motor cortex, and spinal cord of ALS patients in comparison to healthy controls, independently of genotype and other factors (e.g. gender and age) suggesting that disease status determines the extent of dysregulation [121].
A recent multicenter study reported increased levels of CHIT1 in cerebrospinal fluid of both early and late symptomatic ALS patients, reflecting microglial activation; therefore, CHIT1 may be recommended as a potential differential marker for ALS for diagnosis and immune-modulatory therapeutic interventions [122], [123], [124].
Neuromyelitis optica (NMO) is a severe demyelinating autoimmune inflammatory process of the eye nerves (optic neuritis) and the spinal cord (myelitis) [125]. Increased CSF (but not serum) chitinase levels were reported in patients with NMO and relapsing-remitting multiple sclerosis compared with healthy controls and patients with secondary progressive multiple sclerosis and other inflammatory neurological diseases. YKL-40 is a biomarker for NMO spectrum disorders severity and a potential target for its treatment [126].
Multiple sclerosis (MS) is a disease that include axonal injury and loss in the central nervous system, where useful markers are neurofilaments (light and heavy chains), CLPs, soluble surface markers of innate immunity, and oligoclonal immunoglobulin M antibodies [127,128]. The YKL-40 levels were higher at the beginning of the disease and in the clinically isolated syndrome (CIS) group than in the MS group, although they were not involved in the progression to clinically definite MS [129].
CSF levels of YKL-40 and the transcription factor involved in immune cell activity, HoxB3, appear to predict CIS to MS conversion [130]. Dysregulation of TNF and TNF-receptors 1/2 pathways with their associated patterns encompassing high levels of YKL-40, associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome [131]. A potential role of YKL-40 as therapeutic target in MS patients was suggested by an early work showing its neurotoxic effect in vitro [132].
Indeed, chitin accumulates in a lot of tissues and may be particularly toxic to neurons as in with Alzheimer’s disease (AD) [133] a severe neurodegenerative disease. In particular, CSF CHIT1 and YKL-40 levels are increased in individuals with frontotemporal dementia (FTD) syndromes, due to AD pathology [134]. There is growing evidence that chronic neuroinflammation plays a role in FTD. Late-onset AD patients showed significantly higher expression levels of CHIT1 in comparison with healthy subjects suggesting that an immuno-activation of microglia in amyloid plaque pathology [135]. The putative microglial marker CSF CHIT1 might be useful for the identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology [136]. It has been shown that among asymptomatic AD individuals, neuroinflammation (expressed by higher CSF YKL-40) is associated with neural damage [137].
Dementia with Lewy bodies (DLB) is a neurodegenerative dementia, where YKL-40 demonstrated significantly higher protein levels compared to aged individuals with an absence of neurological features [138].
Huntington’s disease (HD) is a progressive decline in cognitive, motor and behaviour functions as a consequence of neuronal dysfunction and death. IL-6, CHIT1 and YKL-40 showed disease-related elevations in CSF in HD patients, supporting the role of microglial activation and the innate immune system in the disease [139].
In inflammatory neurological disorders CSF YKL-40 was significantly elevated in pediatric patients compared to controls, [140]. CHIT1 elevation in treatment-naïve spinal muscular atrophy patients indicated the involvement of (neuro)inflammation also in this disease [141].
The chitinases in gynecological and obstetrical diseases
Polycystic ovary syndrome (PCOS) represents a state of low-grade chronic inflammation where the macrophages could play a role due to obesity, insulin resistance, and other metabolic disorders associated with PCOS itself [142]. Indeed, CHIT1 was elevated in PCOS women compared to controls, independent of obesity [143].
Chitinases activity was also statistically higher in severe endometriosis patients compared to control subjects [144] and in ovaric cancer [145]. A panel of noninvasive inflammatory markers for the diagnosis and severity including YKL-40 indicated a significant correlation between CA 125 (a marker of advanced endometriosis) concentrations and IL-6 and prolactin levels, providing valuable information not only for determining the advanced stage of endometriosis but also for the diagnosis of this disease [146].
CHIT1 can play a role as a biomarker of fetal compromise [147]. In this study umbilical cord CHIT1 levels correlated with umbilical artery flow velocity waveform measured just before delivery and both parameters were high in the pre-eclamptic group; indeed, high CHIT1 reflects the severity of fetoplacental blood flow resistance in pregnancies complicated by preeclampsia [147]. Further, high CHIT1 levels were reported in mild pre-eclampsia women suggesting a role played by activated macrophages in the pathogenesis of this complication of pregnancy [144].
Further, high CHIT1 levels were reported in mild pre-eclampsia women suggesting a role played by activated macrophages in the pathogenesis of this complication of pregnancy [144].
The chitinases in miscellaneous diseases
Non-alcoholic fatty liver disease
Kupffer cells of non-alcoholic fatty liver disease (NAFLD) patients showed an increased CHIT1 gene expression [148]. CHIT1 expression differed markedly in livers of normal controls compared to those of patients with NAFLD or non-alcoholic steatohepatitis (NASH). A significant correlation between mRNA CHIT1 and O2, lipid peroxidation, TNF-α, and ferritin levels was observed in both NASH and NAFLD. CHIT1 may play a role in increasing the risk for a poor outcome in NASH. Moreover, CHI3L1 is a biomarker for HBV- and HCV-induced liver fibrosis and cirrhosis [149, 150].
Familial Mediterranean fever
In one study, CHIT1 level has been found elevated in Familial Mediterranean fever (FMF) patients with correlation with other inflammation markers during fever attack compared to the silent period of the disease [151]. Furthermore, colchicine reduces the expression and activity of CHIT1 by preventing neutrophil leucocytes chemotaxis and macrophage activity [152].
β-Thalassemia
Highest levels of plasma CHIT1 were observed in patients with β-thalassemia major, with the highest degree of iron overload, suggesting that this factor could trigger CHIT1 overproduction [153].
Sarcoidosis
Sarcoidosis is an inflammatory disease characterized by granuloma formation. It preferentially involves the lungs but may affect any other organ and it is often a diagnosis of exclusion, but several biomarkers as lymphocyte subsets and levels of signaling molecules can also be used to improve the accuracy of diagnosis, disease progression, prognosis, and make treatment decisions [154].
Increased CHIT1 is a sensitive biomarker of active sarcoidosis [155] where it can have prognostic value [200] and it may be used in Fever of Unknown Origin to detect sarcoidosis [156]. CHIT1 sensitivity is about 90% exceeding the sensitivity (about 60%) of the commonly used biomarker ACE [157]. CHIT1 in serum and BAL correlated with radiological stages of sarcoidosis [158], whereas corticosteroids reduce the activity of CHIT1 [156, 157]. Similarly, CHIT1, as ACE, reflects the granulomatous burden of the disease [157].
An infectious trigger has long been suspected in sarcoidosis [154, 159]. The candidates are tuberculous and nontuberculous Mycobacterium spp. and Cutibacterium acnes (formerly Propionibacterium acnes), which is the only microorganism to be isolated from sarcoid lesions in 78% of patients with sarcoidosis [160]. Negi et al. [161] developed a monoclonal antibody (anti-P acnes antibody, PAB) that recognizes the cell membrane-bound lipoteichoic acid of C. acnes in sarcoid granulomas. As for CHIT1, ACE has the same genotypic variability problem that produces false negatives, therefore, the combination of ACE and CHIT1 activity assays can improve the predictability of these tests in sarcoidosis [53].
Sarcoidosis shares with hypersensitivity pneumonitis the possibility of fibrotic evolution; YKL-40 distinguishes patients with hypersensitivity pneumonitis from healthy individuals and from patients with idiopathic pulmonary fibrosis. Their sensitivity and specificity confirm their potential role as biomarkers [162].
Juvenile idiopathic arthritis
CHIT1 level measured in synovial fluid patients with Juvenile idiopathic arthritis (JIA) was up to approximately 1,000 nmol/(h mL) at disease onset representing the activity of macrophages in the synovial fluid, whereas the level in the sera was below 600 nmol/(h mL). Positive correlation has been found between the frequency of Th17 and Th17-derived cell subsets and YKL-40 levels in synovial fluid of JIA patients [163].
Cancer
Chitinases levels were significantly higher in patients with high Gleason scores compared to the control group (p<0.001), indicating that it may have a role in the immune reaction to malignant diseases [164, 165], as in patients with primary breast cancer [165].
Glioblastoma multiforme patients with a high expression of CD163 and CHI3L2 had a poor overall survival, prognosis-free survival, and disease-specific survival [166]. The differential expression of the immunomodulatory molecule YKL-40 may affect the treatment efficacy of PI3K/AKT-based pathway inhibitors in glioblastoma [166].
In primary and metastatic tumors, CHI3L2 and the EOMES+ eomesodermin homolog Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1-targeted immunotherapy; collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy [167].
Autoimmune diseases
This topic has been widely reviewed by Tizaoui et al. [168] who collected the literature about the role of YKL-40; the results are conflicting due the fact the papers regard different phases and complication of these diseases.
Indeed, in rheumatoid arthtritis (RA) the chitinase and N-acetyl-glucosaminidase have been identified as indices of telomere dysfunction and are greater in RA patients than those in healthy controls [169] and elevated oxidant stress markers correlate with disease activity, but efficacy as a diagnostic and prognostic marker of this disease, requires further studies (reviewed in [168]).
In psoriasis, YKL-40 level is correlated only to complications as carotid intima-media thickness and defective aortic elasticity [170] and arthritis, often in association with severe disease and response to treatment [171].
In systemic lupus erythematosus (SLE) the average plasma levels of YKL-40 is about twice higher in the SLE group than in controls [172] as in active Behcet’s disease (BD) an elevation in serum YKL-40 levels has been found [173].
In Crohn’s disease, sYKL-40 level was shown higher in patients with intestinal strictures than in those without intestinal strictures [174]. Vind et al. [175] found that sYKL-40 level is increased in 40–50% of ulcerative colitis and Crohn’s disease patients with active disease, and the level was also increased in 30% of patients with clinically inactive Crohn’s disease. Ytting et al. [176] reported a case where s YKL-40 level is increased as an appearance of Sweet’s syndrome in a patient previously diagnosed with ulcerative colitis, sYKL-40 level acted as a marker of disease activity of Sweet’s syndrome. Increased sYKL-40 level was also discovered as the marker of articular involvement in IBD [177].
Overall, all this research can be interpreted as a whole, assuming that chitinases in autoimmune diseases are an expression of acute or disease complications, while are not significantly elevated in chronic forms. These results are expected because chitinases correlate with macrophage activation that occurs in the early stages of autoimmune diseases, when autoantigen is presented.
Other diseases
YLK-40 plays a role in the pathogenic process of Lichen planus where it can help in the treatment strategies [178].
Pyoderma gangrenosum (PG) is a rare, neutrophilic autoinflammatory dermatosis where YKL-40 can be considered a valuable biomarker of inflammation correlated with and IL-6 and C-reactive protein [179].
This chitinase level is increased in hemodialyzed patients, especially in those with cardiovascular disease, and it is independently associated with neopterin – a biomarker of monocyte/macrophage activation; anti-HCV seropositivity enhances plasma YKL-40 levels in these patients [180].
Arthroscopic partial meniscectomy and total knee arthroplasty cartilage expresses distinct sets of osteoarthritis transcripts amongst which CHI3L2 [181].
Interestingly, the serum YKL-40 is a prognostic and sensitive biomarker of all-cause mortality in octogenarians [182].
Take home messages and limitations of this review
In this review, the role of the macrophage activation enzymes chitinases, as potential biomarkers of diagnosis, prognosis, severity, and therapy monitoring has been focused (Table 3). The role of chitinases in the immune system and in many inflammatory-based diseases supports the growing interest in this area of research, aimed to unveil the still uncovered functions of CHIT1 and chitinases in human diseases. The use of chitinases assay has been extended in Italy to third level centres specialised for the diagnosis and staging of sarcoidosis and in the diagnosis of fever of unknown origin [156]. The use in the clinics has spread in other countries, as China, where chronic hepatitis HBV and HCV in fibrotic evolution is a common problem, and therefore this assay is widespread. Multiple developments are expected in this field of research and will expand current knowledge.
However, as the bias of these data is the presence of a null CHIT1 gene subpopulation [53] which is responsible of false-negative values, the assay should be completed with the other markers of macrophagic activity such as ACE and, if necessary, by genetic analysis in low CHIT1 activity patients. Furthermore, the clinical use of blood spot CHIT1 for the screening of lysosomal storage disorders can be quite practical, provided proper cut-off values are determined for each lab [183].
About appropriateness of these tests in the different diseases, the quality specifications of these assays are so good to provide reliable results; but the proportion of false-negative and false-positive results need to be investigated in every specific disease, consistently with the disease stadiation and factors interfering with the development of the disease.
The potential of CHIT1 and chitinases has not been fully explored yet and future studies will produce many surprising discoveries in the immunology and allergology fields of research.
Acknowledgments
The authors would like to thank the Periodic Fevers Research Center of Catholic University, Rome (Italy) and the Prof. Andrea Urbani for providing precious supervision during the preparation of this manuscript.
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Research funding: Periodic Fevers Research Center.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Not applicable.
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Ethical approval: Not applicable.
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