Chitinase 3-like 1 is neurotoxic in primary cultured neurons

Matute-Blanch, Clara; Calvo-Barreiro, Laura; Carballo‐Carbajal, Iria; Gonzalo, Ricardo; Sánchez, Àlex; Vila, Miquel; Montalbán, Xavier; Comabella, Manuel

doi:10.1038/s41598-020-64093-2

Cited by 31 publications

(25 citation statements)

References 10 publications

(12 reference statements)

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“…We can’t make any determination of causality from our study, although the indirect evidence for pathogenicity of CHI3L1 does exist in the literature: subjects with clinically isolated syndrome (CIS) who had high CSF levels of CHI3L1 had greater and faster transition to clinically definite MS and a four-fold increased risk for the development of neurological disability compared to CIS subjects with low CSF CHI3L1 levels ( Comabella et al, 2010 ; Canto et al, 2015 ). Additionally, CHI3L1, in concentrations analogous to those measured in the active MS group in this study was mildly neurotoxic to primary cultured neurons in vitro ( Matute-Blanch et al, 2020 ). The possibility of direct or indirect neurotoxicity of CSF biomarkers associated with CELs is supported by the positive correlation of CHI3L1 (as well as IL-12p40 and TNFα) with cNfL.…”

Section: Discussionmentioning

confidence: 56%

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

et al. 2021

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Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.

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Section: Discussionmentioning

confidence: 56%

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

et al. 2021

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“…For example, inhibition of CHI3L1 with the compound K284-6111 prevented amyloid beta-induced neuroinflammation and impairment of recognition memory via inhibition of the NF-κB pathway in an Alzheimer’s disease mouse model [ 42 ]. In line with this, CHI3L1 was found to be neurotoxic towards cortical neurons but not immune cells [ 43 ]. By contrast, human CHIT1 and CHI3L1 promoted oligodendrogenesis from neural stem cells [ 44 ].…”

Section: Discussionmentioning

confidence: 75%

Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

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“…The CHI3L1 protein induced cytotoxicity in cultured neurons in vitro through a mechanism that is as yet unknown. 40 Moreover, CHI3L1 CSF levels increase in neurodegenerative diseases like Alzheimer disease as patients deteriorate, 41 – 43 and high levels of this protein in amyotrophic lateral sclerosis imply a more accelerated disease course. 44 We showed previously that CHI3L1 was the only independent factor associated with a 1-point EDSS progression and the possibility of receiving a diagnosis of progressive disease in patients with RRMS.…”

Section: Discussionmentioning

confidence: 99%

Potential Role of CHI3L1+ Astrocytes in Progression in MS

Cubas-Núñez

Gil-Perotín

Castillo-Villalba

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveNeurofilament light protein (NfL) and chitinase 3–like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability.MethodsNfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues.ResultsDuring a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration.ConclusionsBoth CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease.Classification of EvidenceThis study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.

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Chitinase 3-like 1 is neurotoxic in primary cultured neurons

Cited by 31 publications

References 10 publications

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Potential Role of CHI3L1+ Astrocytes in Progression in MS

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