Astrocytic Chitinase‐3‐like protein 1 in neurological diseases: Potential roles and future perspectives

Abstract

Chitinase‐3‐like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure‐based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment.

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain

“…It is being considered as a biomarker of disease progression and cognitive impairment in cardiovascular-, neurodegenerative-, autoimmune- and inflammatory diseases (Kjaergaard et al, 2016; Li et al, 2023; Moreno-Rodriguez et al, 2020; Talaat et al, 2023; Tizaoui et al, 2022; Yeo et al, 2019). While its exact mechanisms of action are still unknown, it is speculated that accumulation of chitinase-like proteins are toxic to CNS cells and lead to astrogliosis, potentially impacting cognitive functioning (Li et al, 2023; Lomiguen et al, 2018; Turano et al, 2015). Indeed, increased frontal cortex expression of YKL-40 in neurodegenerative disease has been associated with poorer episodic memory and perceptual speed (Llorens et al, 2017; Moreno-Rodriguez et al, 2020).…”

“…Several studies have shown dysregulated levels of YKL-40 in SMI (Arion et al, 2007; Dieset et al, 2019; Horváth and Mirnics, 2014; Jakobsson et al, 2015; Rolstad et al, 2015; Zhao et al, 2007). It is being considered as a biomarker of disease progression and cognitive impairment in cardiovascular-, neurodegenerative-, autoimmune- and inflammatory diseases (Kjaergaard et al, 2016; Li et al, 2023; Moreno-Rodriguez et al, 2020; Talaat et al, 2023; Tizaoui et al, 2022; Yeo et al, 2019). While its exact mechanisms of action are still unknown, it is speculated that accumulation of chitinase-like proteins are toxic to CNS cells and lead to astrogliosis, potentially impacting cognitive functioning (Li et al, 2023; Lomiguen et al, 2018; Turano et al, 2015).…”

Proteomic Insights into Metastatic Breast Cancer Response to Brain Cell-Secreted Factors

“…expression by activated astrocytes may play a role in tumor progression, angiogenesis, immune escape, and resistance to therapeutic drugs [53]. It is also worth highlighting osteopontin (SPP1) which plays a crucial role in driving metastasis, invasion, angiogenesis, chemotaxis, and suppression of anti-tumor immune responses [54].…”

Inhibition of Amyloid-β (Aβ)-Induced Cognitive Impairment and Neuroinflammation in CHI3L1 Knockout Mice through Downregulation of ERK-PTX3 Pathway

“…CHI3L1 is expressed in several types of cell types, including neutrophils, macrophages, chondrocytes, and fibroblast-like synovial cells [11,14]. CHI3L1 has been widely studied as it has been found to be significantly involved in various diseases in the peripheral system, including asthma, arthritis, sepsis, diabetes, liver fibrosis, coronary artery disease, and several cancers, but its role in brain health and disease has not been investigated much even though it is expressed not only in peripheral systems but also in the CNS such as microglia and astrocytes [14][15][16][17]. Overexpression of CHI3L1, produced by cells (neutrophils, macrophages, fibroblast-like cells, T-lymphocytes, and endothelial cells) involved in chronic inflammation, is considered a hallmark of various inflammatory conditions [18,19].…”