Abstract
Chitinase 3-like 1 (CHI3L1) is known to play a role as prognostic biomarker in the early stages of multiple sclerosis (MS), and patients with high cerebrospinal fluid CHI3L1 levels have an increased risk for the development of neurological disability. Here, we investigated its potential neurotoxic effect by adding recombinant CHI3L1 in vitro to primary cultures of mouse cortical neurons and evaluating both neuronal functionality and survival by immunofluorescence. CHI3L1 induced a significant neurite length retraction after 24 and 48 hours of exposure and significantly reduced neuronal survival at 48 hours. The cytotoxic effect of CHI3L1 was neuron-specific and was not observed in mouse immune or other central nervous system cells. These results point to a selective neurotoxic effect of CHI3L1 in vitro and suggest a potential role of CHI3L1 as therapeutic target in MS patients.
Highlights
Chitinase 3-like 1 (CHI3L1) is known to play a role as prognostic biomarker in the early stages of multiple sclerosis (MS), and patients with high cerebrospinal fluid CHI3L1 levels have an increased risk for the development of neurological disability
Within the central nervous system (CNS), CHI3L1 is mainly secreted by reactive astrocytes[2,6], in lesions with high inflammatory activity, and by macrophages/microglial cells in lesions with low inflammatory activity[2]
A recent validation study conducted by our group in more than 800 cerebrospinal fluid (CSF) samples confirmed a role of CHI3L1 as prognostic biomarker in clinically isolated syndrome (CIS) patients[2]
Summary
Chitinase 3-like 1 (CHI3L1) is known to play a role as prognostic biomarker in the early stages of multiple sclerosis (MS), and patients with high cerebrospinal fluid CHI3L1 levels have an increased risk for the development of neurological disability. The cytotoxic effect of CHI3L1 was neuron-specific and was not observed in mouse immune or other central nervous system cells These results point to a selective neurotoxic effect of CHI3L1 in vitro and suggest a potential role of CHI3L1 as therapeutic target in MS patients. Proteomic findings were validated by ELISA and CHI3L1 levels were significantly increased in the CSF of MS converters and high levels were associated with a shorter time to MS compared to non-MS converters[1] Based on these initial promising results, our group conducted a validation study of CHI3L1 as prognostic biomarker in the CSF of 813 CIS patients from 15 MS centres classified according to their conversion to MS based on clinical and radiological criteria[2]. Considering that neuronal damage is responsible for the permanent neurologic disability observed in MS patients[3,4], in the present study we aimed to explore the potential neurotoxic effect of CHI3L1 by adding the protein at different concentrations in vitro to primary neuronal cultures
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