Chitotriosidase: a marker and modulator of lung disease

Chang, Dan; Sharma, Lokesh; Cruz, Charles S. Dela

doi:10.1183/16000617.0143-2019

Cited by 40 publications

(21 citation statements)

References 121 publications

(151 reference statements)

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“…Previously identified macrophage subsets included intravascular macrophages (expressing LYVE1 and MAF ) (Chakarov et al 2019; Evren et al 2021), Macro-AW-CX3CR1 (Chakarov et al 2019; Pirzgalska et al 2017; Y. Wolf et al 2017; Hulsmans et al 2017), Macro-CHIT1 (CHIT1 expressing with roles in asthma, COPD and lung fibrosis) (Travaglini et al 2020; Chang, Sharma, and Dela Cruz 2020) and interstitial macrophages (Macro-interstitial expressing chemokines CXCL9, 10 and 11 )(Evren et al 2021). We identified a new cluster expressing both monocyte CD14 and macrophage markers, termed Macro-intermediate (Figure S9a).…”

Section: Resultsmentioning

confidence: 99%

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Madissoon

Oliver

Kleshchevnikov

et al. 2021

Preprint

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SummaryMultiple distinct cell types of the human lung and airways have been defined by single cell RNA sequencing (scRNAseq). Here we present a multi-omics spatial lung atlas to define novel cell types which we map back into the macro- and micro-anatomical tissue context to define functional tissue microenvironments. Firstly, we have generated single cell and nuclei RNA sequencing, VDJ-sequencing and Visium Spatial Transcriptomics data sets from 5 different locations of the human lung and airways. Secondly, we define additional cell types/states, as well as spatially map novel and known human airway cell types, such as adult lung chondrocytes, submucosal gland (SMG) duct cells, distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts and Schwann cells. Finally, we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, and B and T lineage immune cells. Using our transcriptomic data for cell-cell interaction analysis, we propose a signalling circuit that establishes and supports this niche. Overall, we provide a transcriptional and spatial lung atlas with multiple novel cell types that allows for the study of specific tissue microenvironments such as the newly defined gland-associated lymphoid niche (GALN).

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Section: Resultsmentioning

confidence: 99%

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Madissoon

Oliver

Kleshchevnikov

et al. 2021

Preprint

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“…Many plant chitinases belong to the family of glycosyl hydrolases 18 (GH18), a protein family that exists in plants, fungi, bacteria, actinomycetes, insects and humans [13][14][15]. In addition to acidic mammalian chitinase, humans produce chitotriosidase (CHIT1, also abbreviated as HCHT) [16]. CHIT1 is expressed by neutrophils, macrophages or epithelial cells [17][18][19] and the dominant chitinase in the human lung [20].…”

Section: Introductionmentioning

confidence: 99%

Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing

Chang

Gloria

Hellmann

et al. 2022

Preprint

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Chitin is a highly abundant polysaccharide in nature and linked to immune recognition of fungal infections and asthma in humans. Ubiquitous in fungi and insects, chitin is absent in mammals and plants and, thus, represents a microbe-associated molecular pattern (MAMP). However, the highly polymeric chitin is insoluble, which potentially hampers recognition by host immune sensors. In plants, secreted chitinases degrade polymeric chitin into diffusible oligomers, which are "fed to" innate immune receptors and co-receptors. In human and murine immune cells, a similar enzymatic activity was shown for human chitotriosidase (CHIT1) and oligomeric chitin is sensed via an innate immune receptor, Toll-like receptor (TLR) 2. However, a complete system of generating MAMPs from chitin and feeding them into a specific receptor/co-receptor-aided sensing mechanism has remained unknown in mammals. Here, we show that the secreted chitinolytic host enzyme, CHIT1, converts inert polymeric chitin into diffusible oligomers that can be sensed by TLR1-TLR2 co-receptor/receptor heterodimers, a process promoted by the lipopolysaccharide binding protein (LBP) and CD14. Furthermore, we observed that Chit1 is induced via the beta-glucan receptor Dectin-1 upon direct contact of immortalized human macrophages to the fungal pathogen Candida albicans, whereas the defined fungal secreted aspartyl proteases, Sap2 and Sap6, from C. albicans were able to degrade CHIT1 in vitro. Our study shows the existence of an inducible system of MAMP generation in the human host that enables contact-independent immune activation by diffusible MAMP ligands with striking similarity to the plant kingdom. Moreover, this study highlights CHIT1 as a potential therapeutic target for TLR2-mediated inflammatory processes that are fueled by oligomeric chitin.

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“…In the present study, all sarcoidosis patients were diagnosed according to the international guidelines, confirmed by histology [15]. CHIT1 is mainly produced by activated macrophages both in normal and inflammatory conditions [20,21]; therefore, it can be significantly increased in a wide range of diseases involving the macrophages or microglial hyperactivation, such as Gaucher disease, tuberculosis, sarcoidosis, malaria, leishmaniosis, beta thalassemia, multiple sclerosis, and Alzheimer's disease [20,[22][23][24]. CHIT1 is a member of family 18 of the glycosyl hydrolases.…”

Section: Discussionmentioning

confidence: 90%

The Use of Chitotriosidase as a Marker of Active Sarcoidosis and in the Diagnosis of Fever of Unknown Origin (FUO)

Francesco

Verrecchia

Sicignano

et al. 2021

JCM

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Sarcoidosis is a multi-organ inflammatory granulomatosis with a lung-predominant involvement. The aim of this study was to investigate the use of serum chitotriosidase (CHIT1) in patients with fever of unknown origin (FUO); the patients with confirmed diagnosis of active sarcoidosis were compared with ones affected by inactive or treated sarcoidosis. CHIT1 activity was evaluated in 110 patients initially admitted at the hospital as FUOs. The overall performance of CHIT1 for active sarcoidosis diagnosis was assessed by performing an area under the receiver operating characteristic curve analysis (AUROC). The sarcoidosis patients were significantly older than the FUO patients not affected by sarcoidosis (p < 0.01). CHIT1 showed a good accuracy as a biomarker for active sarcoidosis in patients explored for FUO (AUROC 0.955; CI 95% 0.895–0.986; p < 0.001). A CHIT1 value >90.86 showed 96.8% sensitivity (84.2–99.9) and 85.5% specificity (75–92.8) in discriminating active sarcoidosis from other causes of FUO. CHIT1 significantly discriminated active versus inactive/under treatment sarcoidosis patients (with lower enzyme activity) (ROC analysis, sensitivity: 96.9%, specificity: 94.7%, value >83.01 nmol/mL/h, AUROC: 0.958, 0.862–0.994, p < 0.001) compared to ACE (ROC analysis, sensitivity: 25.8%, specificity: 93.7%, value >65 UI/L). In conclusion, CHIT1 is a reliable/sensitive biomarker of active sarcoidosis, with values significantly decreasing in remitted/treated patients. It significantly discriminates active sarcoidosis from FUO patients, providing a useful tool in the diagnosis-assessing process.

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Chitotriosidase: a marker and modulator of lung disease

Cited by 40 publications

References 121 publications

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing

The Use of Chitotriosidase as a Marker of Active Sarcoidosis and in the Diagnosis of Fever of Unknown Origin (FUO)

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