The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review

Abstract

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.

Keywords: Autoimmune disease; Biomarker; Diagnostic marker; Pathogenesis; YKL-40.

Figure 1

Role of YKL-40 in RA pathogenesis. (A) YKL-40 binds to the HLA-DR4, inducing mononuclear cell proliferation through HLA-DM dependent MHC II-mediated presentation of APCs. Intracellular HLA-DM also plays an important role in the presentation of YKL-40 to CD4+ T cells via "epitope editing”. YKL-40 induces mononuclear cell proliferation by binding to the HLA-DR4 peptide binding motif (B) YKL-40 also activates FAK/PI3K/Akt pathway in osteoblast, resulting in IL-18 production and EPC angiogenesis through inhibition of miR-590-3p. This in turn stimulates endothelial progenitor cell (EPC) angiogenesis, promoting inflammation, a process critical in the pathogenesis of RA. Abbreviations: RA: rheumatoid arthritis; HLA: human leukocyte antigen; MHC: major histocompatibility complex; APC: antigen presenting cell; FAK: focal adhesion kinase; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; IL-18: interleukin-18; EPC: endothelial progenitor cell; miR: microRNA.