Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications

Abstract

Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.

Keywords: Alzheimer’s disease; Biomarker; Brain tumors; CHI3L1; Ischemic cerebral stroke; Multiple sclerosis; Neurodegeneration; Neuroinflammation; Therapeutic targeting; Traumatic brain injury.

Fig. 1

CHI3L1 and its Role in the Pathogenesis of Acute and Chronic Brain Disorders. CHI3L1 contributes to neuronal death, degeneration, increased blood–brain barrier (BBB) permeability, neuroinflammation, and angiogenesis. Activated microglia and reactive astrocytes play a central role in these brain conditions. The activation of these glial cells leads to the release of inflammatory cytokines, such as IL-6, TNF-α, IL-1β, and IFN-γ, causing neuronal damage and driving the progression of brain diseases

Fig. 2

CHI3L1-induced tumor angiogenesis, growth, migration, invasion, and inflammation. CHI3L1, secreted by tumors, stimulates angiogenesis by activating endothelial cells through the coupling of the membrane receptor syndecan-1 with integrin and upregulating the expression of VEGF via the ERK1/2 and AKT pathways. CHI3L1 promotes tumor growth and migration by interacting with TGF-β1 and its receptor TGFR, thereby activating the SMAD2/SMAD3 signaling pathway. Additionally, CHI3L1 interacts with CD44 and IL-13Rα2, further activating the AKT and ERK1/2 pathways, which enhance tumor growth and invasion. CHI3L1 also promotes invasion via MMP-9 and induces the secretion of CXCL8 and IL-6, driving inflammation and tumor progression

Fig. 3

CHI3L1 Interactions and Intracellular Signaling Pathways in Neuroinflammation and Tumor Progression. CHI3L1 interacts with various cell surface receptors, including IL-13Rα2, syndecan-1/αvβ3, and RAGE, triggering multiple intracellular signaling pathways. These interactions lead to diverse cellular outcomes, such as the regulation of apoptosis, tumor metastasis, inflammation, carcinogenesis, and tumor angiogenesis. Interaction with syndecan-1 induces angiogenesis through integrin αvβ3 and MAPK signaling. CHI3L1’s interaction with RAGE activates the Wnt/β-catenin pathway, promoting tumor progression by facilitating immune evasion and migration. Similarly, interactions with IL-13Rα2 drive carcinogenesis and tumor angiogenesis via Erk1/2, Wnt/β-catenin, and Akt signaling pathways. Additionally, CHI3L1 modulates brain inflammation and neurodegenerative disorders by influencing the IL-13 signaling pathway through IL-13Rα2, enhancing the secretion of inflammatory cytokines such as IL-1β and IL-6, and activating pathways like AKT and ERK1/2

Fig. 4

The role of CHI3L1 in ischemic stroke progression. The absence of CHI3L1 accelerates stroke progression, as observed in CHI3L1 knockout models. In these models, there was an increased release of proinflammatory cytokines such as IL-6 and IL-1β, along with a decreased release of anti-inflammatory cytokines like IL-10 and IL-4. Additionally, there was heightened expression of inflammation-related proteins, including iNOS, COX-2, Iba-1, and GFAP. As a result, the deletion of CHI3L1 exacerbates neuroinflammation and neuronal cell death following ischemia, further accelerating stroke progression

Fig. 5

Neuroinflammatory conditions modulated by CHI3L1 under the condition of TBI. Inflammatory responses are characterized by leukocyte infiltration into the CNS parenchyma and a significant loss of BBB integrity. The influx of leukocytes is linked to the disruption of homeostatic microglial functions, including immunosurveillance, phagocytosis, and immune resolution. Furthermore, CHI3L1 promotes astrocyte migration and proliferation, further exacerbating the inflammatory response. This cascade contributes to increased neuronal damage and the progression of secondary injury following TBI

Fig. 6

IL13Rα2 signaling pathways mediated by CHI3L1. CHI3L1 binds to IL13Rα2, activating MAPKs such as ERK1/2 and JNK, along with the PI3K/Akt and NF-κB pathways, to regulate apoptosis, pyroptosis, and inflammasome activation. The binding of IL13Rα2 to TMEM219 further enhances the anti-apoptotic response triggered by CHI3L1 stimulation

Fig. 7

CHI3L1’s role in the pathology of Alzheimer’s disease through modulation of neuroinflammation. As chronic inflammation progresses, astrocytes and microglia release proinflammatory mediators, including CHI3L1, cytokines, and chemokines. CHI3L1 regulates IL-6 levels, which in turn elevates IL-1β and TNF-α levels, disrupting the BBB and initiating neuroinflammation, ultimately leading to neuronal death. IL-6 activation stimulates astrocytes, with reactive astrocytes (marked by increased GFAP) promoting amyloid-beta (Aβ) aggregation and Tau phosphorylation. Through STAT3 activation, CHI3L1 promotes APP expression in neurons, further driving Aβ aggregation and cognitive decline. Additionally, CHI3L1 induces microglial activation by regulating IL-6, resulting in the production of IL-6, IL-1β, and TNF-α, which exacerbates neuroinflammation and disrupts neurotransmitter signaling. CHI3L1 also activates the MAPK and NF-κB pathways, contributing to Aβ accumulation and neuronal inflammation via RAGE activation in both astrocytes and neurons

Fig. 8

CHI3L1 pathogenesis and glial-immune cell interactions in PD. In PD, proinflammatory cytokines produced by Th1 and Th17 cells activate astrocytes and microglia, leading to the apoptosis of DA neurons. Conversely, Treg and Th2 cells may provide protection against neuroinflammation. The accumulation of α-synuclein initiates PD, thereby activating astrocytes and microglia. CHI3L1 regulates cytokines, which further activate microglia and astrocytes. Activated microglia release TNF-α, IL-1β, IL-6, and NO, which contribute to DA neuron degeneration. Microglia also activate astrocytes, resulting in secretion of IL-6, IL-1α, IL-1β, and NO. Overall, T cells, astrocytes, microglia, and CHI3L1 collaborate to sustain neuroinflammation and DA neuron loss in PD patients

Fig. 9

Mechanisms of CHI3L1 and immune cell pathogenicity in multiple sclerosis. In multiple sclerosis, T-lymphocytes and B-lymphocytes breach the permeable blood–brain barrier and enter the CNS. Interactions between T-lymphocytes, B-lymphocytes, and microglia lead to the release of antibodies and cytokines, including secreted CHI3L1, which can become pathogenic during inflammation. Antibodies may induce vascular damage and CNS inflammation through complement-dependent or antibody-dependent cellular cytotoxicity, mediated by Fc receptors on microglia and macrophages. Autoreactive B-lymphocytes infiltrate the brain, resulting in elevated intrathecal antibody production. The binding of CHI3L1 and antibodies to target cells may directly cause damage or alter cellular function, leading to demyelination. Additionally, secreted CHI3L1 and antibodies can indirectly promote demyelination by activating autoreactive T-lymphocytes, microglia, and macrophages

Fig. 10

Therapeutic strategies targeting the CHI3L1/IL13Rα2 pathway in the tumor microenvironment involve the use of blocking antibodies or inhibitors. Immunosuppressive macrophages, activated by PD-L1/PD-1 signaling, induce CHI3L1 expression in tumor cells, leading to the activation of naive macrophages and promoting the accumulation of immunosuppressive macrophages in the tumor microenvironment. This accumulation fuels tumor progression