Significance of chitinase-3-like protein 1 in the pathogenesis of inflammatory diseases and cancer

Abstract

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly upregulated by various inflammatory and immunological diseases, including several cancers, Alzheimer's disease, and atherosclerosis. Several studies have shown that CHI3L1 can be considered as a marker of disease diagnosis, prognosis, disease activity, and severity. In addition, the proinflammatory action of CHI3L1 may be mediated via responses to various proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 may contribute to a vast array of inflammatory diseases. However, its pathophysiological and pharmacological roles in the development of inflammatory diseases remain unclear. In this article, we review recent findings regarding the roles of CHI3L1 in the development of inflammatory diseases and suggest therapeutic approaches that target CHI3L1.

Fig. 1. Relationship between CHI3L1 and various diseases.

The circle sizes are determined based on text-mining scores. The values in the circle symbols are the text-mining scores determined via Open Targets Platform analysis.

Fig. 2. The role of CHI3L1 in signaling pathways for the development of various diseases.

Various cells, such as monocytes, neutrophils, macrophages, epithelial cells, Kupffer cells, osteoclasts, chondrocytes, smooth muscle cells, astrocytes, and cancer cells, produce CHI3L1 by the stimulation of several interleukins, such as IL-13, IL-6, IL-1β, and TNF-α. CHI3L1 expression is inhibited by miR-24, miR-342-3p, miR-449, miR125p-39, and miR-96-5p. The activated cells can release (or produce) IL-1β, TNF-α, IL-6, IL-8, IL-10, IL-12, NO, CXCL9, and CXCL11. In the development of atherogenesis, CHI3L1 directly induces PDGF and PDGFR expression to activate VSMCs and/or directly induces VCAM1 and eNOS expression in the cytosol to cause EC inflammation. In the development of neurodegenerative diseases, CHI3L1 activates the MAPK and NF-кB signaling pathways to induce Aβ accumulation and neuronal inflammation via RAGE in either astrocytes or neurons. In neuronal cells, CHI3L1 activity leads to increased expression of CD14 and TLR4 through the MAPK and NF-кB signaling pathways to damage neurons. In cancer development, several receptors and signaling pathways are involved in these processes. CHI3l1 binds to its receptor IL-13Rα2 by associating with TMEM219 directly or by physically interacting with CD44. The TMEM219-dependent pathway prevents cell death by activating the ERK1/2 and AKT pathways, but direct interaction with IL-13Rα2 causes apoptosis through activation of Wnt/β-catenin. Physical interaction with CD44 activates the AKT pathway to induce metastasis and invasion. The membrane receptors syndecan-1 and integrin α_vβ₅ trigger CHI3L1 signaling pathways, causing tumor vascular permeability and growth by activating the β-catenin, FAK, and ERK 1/2 (MAPK) pathways. CHI3L1 also binds to RAGE and thus activates the FAK and STAT3 pathways, inducing tumor growth. In addition, CHI3L1 elevates the expression of VEGF and its receptor to cause angiogenesis via the activation of the JNK and p38 signaling pathways.

Fig. 3. The relationship between CHI3L1 and cancers.

The circle sizes are determined based on text-mining scores. The values in the circle symbols are the text-mining scores determined via Open Targets Platform analysis.

Fig. 4. The interaction network between CHI3L1 and its target proteins and the roles of CHI3L1 in signaling pathways for the development of cancers.

a Lung cancer. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: In lung cancer, elevated CHI3L1 levels are linked to increased VEGF expression, promoting angiogenesis and tumor progression. CHI3L1 upregulates VEGF through pathways such as ERK1/2 and Akt. CHI3L1 inhibits apoptosis through interactions with the TRAIL signaling pathway, involving TNFRSF10A and CASP8/CAS10. CHI3L1 can bind to TMEM219 and promote tumor growth and invasion by activating Erk1/2 and Akt signaling. CHI3L1 regulates the IL-13 signaling pathway through IL-13Rα2, leading to increased secretion of cytokines, such as IL-1β and IL-6, which can influence inflammation in lung cancer. There have been no reported associations between CHI3L1 and CHID1. However, it has been observed that CHID1 increases M0 macrophage infiltration. b Liver cancer, upper panel; the circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: Elevated CHI3L1 levels increase VEGFA expression through the ERK1/2 and Akt pathways, promoting angiogenesis in liver cancer. CHI3L1 may promote tumor growth and migration by interacting with TGF-β1 and TGFR, thereby activating the SMAD2/SMAD3 signaling pathway. CHI3L1 interacts with IL-13 and IL-13Rα2 to activate the IL-13 signaling pathway, including the AKT and ERK1/2 pathways. Additionally, CHI3L1 affects MMP9, promoting tumor invasion and metastasis. CHI3L1 interacts with RAGE, leading to an increase in IL-6 secretion and inflammation. On the other hand, CHI3L1 may negatively regulate S100A9 and S100A4, which means that its interaction with S100A9 and S100A4 results in a reduction in the proinflammatory effects of S100A9 and S100A4 in liver cancer. c Colorectal cancer. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: CHI3L1 leads to an increase in VEGF/VEGFA expression through the activation of the ERK1/2 and Akt pathways, promoting angiogenesis and tumor progression in colorectal cancer. CHI3L1 has the potential to enhance tumor growth and migration by interacting with TGF-β1 and TGFR, which subsequently activates the SMAD2/SMAD3 signaling pathway. CHI3L1 interacts with CD44 and IL-13Ra2, activating pathways such as AKT and ERK1/2, which in turn promote tumor growth and invasion. Additionally, CHI3L1 affects MMP-9, contributing to tumor invasion. Furthermore, CHI3L1 induces the secretion of CXCL8 and IL-6, which are proinflammatory cytokines that can also play a role in tumor progression and invasion. The relationship between CHI3L1 and ID3 is not well established. However, the interplay between ID3-induced p27KIP1 and RhoA inhibition can contribute to tumor remodeling in colorectal cancer.

Fig. 5. The relationship between CHI3L1 and neurological diseases.

a The circle sizes are determined based on the text-mining score. The values in circle symbols are the text-mining scores determined via Open Targets Platform analysis. b The circle sizes are determined based on the gda score. The values in the circle symbols are the gda scores determined via DisGeNET analysis.

Fig. 6. The interaction network between CHI3L1 and its target proteins and the roles of CHI3L1 in signaling pathways for the development of neurological diseases.

a Alzheimer’s disease. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: CHI3L1 regulates IL-6, inducing an increase in IL-1β and TNF-α. This pathway leads to the disruption of the blood‒brain barrier (BBB) and triggers neuroinflammation, ultimately resulting in neuronal death. IL-6 activates astrocytes, and reactive astrocytes (with increased GFAP) induce Aβ aggregation and Tau phosphorylation. They can also induce Aβ aggregation through the ApoE4 pathway, ultimately leading to neuronal death and cognitive impairment. CHI3L1 downregulates VSNL1 and increases Tau phosphorylation. CHI3L1 activates STAT3 and increases APP expression in neuronal cells, resulting in Aβ aggregation and cognitive impairment. b Schizophrenia. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: CHI3L1 regulates IL-6, inducing microglial activation. Activated microglia express IL-6, IL-1β, and TNF-α, which leads to neuroinflammation and triggers abnormal neurotransmitter signaling. Ultimately, this process results in schizophrenia and related behavioral and immune dysfunction. The association score between CHI3L1 and CRP is high, indicating a strong correlation. However, the specific interaction between these two factors has not yet been identified. CRP is increased by inflammatory cytokines (IL-6, IL-1β, and TNF-α) and induces systemic inflammation, leading to immune dysfunction via the AKT1 pathway. CHI3L1 regulates TNF-α and induces immune dysfunction through the CD14-TLR4 pathway.

Fig. 7. The relationship between CHI3L1 and cardiovascular diseases.

a The circle sizes are determined based on the text-mining score. The values in the circle symbols are the text-mining scores determined via Open Targets Platform analysis. b The circle sizes are determined based on the gda score. The values in the circle symbols are the gda scores determined via DisGeNET analysis.

Fig. 8. The interaction network between CHI3L1 and its target proteins and the roles of CHI3L1 in signaling pathways for the development of cardiovascular diseases.

a Hypertension. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: In the development of hypertension, CHI3L1 stimulates pulmonary artery vascular smooth muscle proliferation through interaction with CRTH2, a G protein-coupled receptor. CHI3L1 binds with IL-13Rα2/TMEM219 and mediates anti-apoptotic effects in pulmonary arterial endothelial cell death through synergy with TGF-ß1 and hypoxia, promoting endothelial permeability and endo-MT transition. This causes spontaneous pulmonary vascular remodeling and hypertension. b Atherosclerosis. Upper panel: The circle sizes are determined based on the score. The values in the circle symbols are the scores determined by STRING analysis. Lower panel: In atherogenesis, CHI3L1 induces endothelial activation and inflammation through synergy with IL-6 and increases VEGFA and CCL2 levels. CHI3L1 potentiates PDGF-BB-induced vascular smooth muscle cell migration and proliferation and probably elevates the VEGFA signaling pathway. As a result, endothelial dysfunction and the onset of atherosclerosis are induced.