| YKL‑40, also known as chitinase‑3‑like protein 1 (CHI3L1), is a secreted glycosyl hydrolase family 18 chitinase‑like glycoprotein that lacks enzymatic chitinase activity but retains a conserved carbohydrate‑binding groove and functions as an immune and tissue‑remodeling regulator at the interface of inflammation, matrix turnover, and cell survival. The protein adopts a β‑sandwich TIM‑barrel‑like fold with a chitin‑binding motif that engages glycan ligands and cell‑surface components, supporting interactions with receptors such as CRTH2 and with pattern‑recognition pathways, while substitutions in the canonical catalytic motif prevent hydrolysis and define CHI3L1 as a lectin‑like effector rather than a degradative enzyme. CHI3L1 expression localizes to activated macrophages, chondrocytes, synovial fibroblast‑like cells, vascular smooth muscle cells, airway epithelium, hepatic stellate cells and astrocytes, and its secretion into the extracellular space positions it to modulate inflammatory microenvironments, extracellular matrix architecture and cell–matrix adhesion in joint, vascular, pulmonary and central nervous system tissues. At the signaling level, CHI3L1 engagement of colonic epithelial cells activates the PI3K–Akt pathway via its carbohydrate‑binding motif and promotes phosphorylation of Akt and downstream targets, supporting cell survival, proliferation and migration under inflammatory conditions, and interacting with Toll‑like receptor 4–dependent cascades that integrate microbial and damage signals in the intestinal mucosa. In the brain, CHI3L1 is predominantly produced by reactive astrocytes and acts as a key regulator of neuroinflammatory tone; activation of CHI3L1 signaling in neural stem and progenitor cells occurs through the G protein–coupled receptor CRTH2 and triggers an intracellular IKKβ–S6K1–S6 axis that suppresses hippocampal neurogenesis, while a related CHI3L1–CRTH2–β‑catenin pathway inhibits β‑catenin signaling and reduces neuronal differentiation. These signaling routes link CHI3L1 to control of neural stem‑cell pool size, neuronal survival, amyloid production and tau phosphorylation in Alzheimer‑associated contexts, and position the protein as an active mediator of neurotoxic inflammatory states rather than only a passive biomarker. CHI3L1 also functions as a mediator of tissue remodeling and fibrosis by influencing fibroblast, endothelial and immune‑cell behaviors, coordinating matrix metalloproteinase expression, collagen turnover and angiogenic responses that shape chronic inflammatory lesions and tumor stroma. Elevated circulating and tissue CHI3L1 associates with osteoarthritis, rheumatoid and other autoimmune diseases, chronic lung disease and a wide range of solid tumors, where its pro‑survival, migratory and angiogenic influences on epithelial, endothelial and stromal cells correlate with disease severity, poor prognosis and resistance to therapy. |
