Potential Roles and Future Perspectives of Chitinase 3-like 1 in Macrophage Polarization and the Development of Diseases

Abstract

Chitinase-3-like protein 1 (CHI3L1), a chitinase-like protein family member, is a secreted glycoprotein that mediates macrophage polarization, inflammation, apoptosis, angiogenesis, and carcinogenesis. Abnormal CHI3L1 expression has been associated with multiple metabolic and neurological disorders, including diabetes, atherosclerosis, and Alzheimer's disease. Aberrant CHI3L1 expression is also reportedly associated with tumor migration and metastasis, as well as contributions to immune escape, playing important roles in tumor progression. However, the physiological and pathophysiological roles of CHI3L1 in the development of metabolic and neurodegenerative diseases and cancer remain unclear. Understanding the polarization relationship between CHI3L1 and macrophages is crucial for disease progression. Recent research has uncovered the complex mechanisms of CHI3L1 in different diseases, highlighting its close association with macrophage functional polarization. In this article, we review recent findings regarding the various disease types and summarize the relationship between macrophages and CHI3L1. Furthermore, this article also provides a brief overview of the various mechanisms and inhibitors employed to inhibit CHI3L1 and disrupt its interaction with receptors. These endeavors highlight the pivotal roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of metabolic diseases, neurodegenerative diseases, and cancers.

Keywords: CHI3L1; cancers; diseases; inhibitors; macrophage polarization.

Figure 1

Homologous sequence alignment, crystal structure, and heparin-binding site of CHI3L1. (a) Homologous sequence alignment of CHI3L1 from six different species, including Homo sapiens, Mus musculus, Rattus norvegicus, Bos Taurus, Sus scrofa, and Macaca mulatta; (b) Crystal structure of CHI3L1 (PDB code: 1NWR); (c) Proposed amino acids (R143, R144, D145, K146) in heparin-binding motif shown in blue and amino acids (K337, K342, R344) in actual binding sites shown in red.

Figure 2

CHI3L1 as a diagnostic and staging biomarker in liver fibrosis progression. In the progression of liver fibrosis, CHI3L1 is secreted and expressed by hepatocytes, hepatic stellate cells, and Kupffer cells in the liver, thus making it a promising diagnostic and staging biomarker for liver fibrosis.

Figure 3

Inhibition of the NF-κB signaling pathway by small-molecule inhibitors: In AD progression, CHI3L1 is primarily secreted by microglia and astrocytes. Small molecule inhibitors reduce the expression of genes such as iNOS, and COX-2 by inhibiting the activation of the NF-κB signaling pathway, slowing down the deposition of amyloid plaques, and improving disease progression.

Figure 4

Activation of signaling pathways and biological effects induced by CHI3L1 interaction with different receptors: The interaction of CHI3L1 from different sources with various receptor sets activates signaling pathways such as JNK, ERK, and PI3K, promoting the polarization and infiltration of M2 macrophages. This, in turn, leads to angiogenesis and tumor metastasis.