Inflammatory‐sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IDD) is the main cause of low back pain and the mechanism of which is far from fully revealed. Although inflammation directed nucleus pulposus (NP) extracellular matrix metabolism dysregulation is known to be the main cause of the degeneration process, few is known about the protective factors. Using high‐throughput label‐free proteomics, we found that inflammation‐related autocrine factor Chitinase‐3‐like protein 1 (CHI3L1, or YKL‐40) is highly expressed in the NP cells during degeneration. Immunohistochemical analysis show that the expression of CHI3L1 is NP tissue specific, and increase significantly during degeneration. Overexpression of CHI3L1 significantly decrease the catabolism, and increase the anabolism of extracellular matrix. Knockdown of CHI3L1 using siRNAs show the opposite results, which imply that the protective role of CHI3L1 in IDD. Using high‐throughput RNA sequencing and functional analyses, we find that AKT3 expression and its phosphorylation is mainly regulated by CHI3L1. And lastly, the mechanism of which is also validated using human and mouse degenerated NP tissues. In summary, our findings show that the inflammation‐related autocrine factor CHI3L1 is NP specific, and it protects IDD by promoting the AKT3 signaling, which may serve as a potential therapeutic target in intervertebral disc degeneration.

M2a Macrophage-Secreted CHI3L1 Promotes Extracellular Matrix Metabolic Imbalances via Activation of IL-13Rα2/MAPK Pathway in Rat Intervertebral Disc Degeneration

“…Consistent with the findings in studies of tumors, we found that M2a macrophages secreted CHI3L1 proteins, thereby promoting ECM degradation. However, we noted that our findings were different from those of Wang et al (34), who recently suggested that CHI3L1 may be a protective factor against IDD. In their experiments, CHI3L1 overexpression or knockdown was performed in NP cells to explore the role of CHI3L1 expression in those cells.…”

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

“…51 We also found that C5 and C6 highly expressed genes reflecting protective characteristics (KLF2 and CHI3L1) (Fig. 2e) 54,55 and existed in the dormant stage of proliferation (Fig. 2f).…”

Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers

“…Based on these preliminary results we posit that CHIL3L1 is one of the key players in driving the healing phenotype of HE-Fibro by expressing proinflammatory and ECM genes together to improve wound repair. Several lines of evidence have previously implicated CHI3L1 in dampening of chronic inflammation [53], promoting M1 macrophage activation [54] and stimulating fibroblast proliferation [55] and ECM remodeling [56]. DEGs analysis on these DFU-Healers vs. other fibroblast clusters revealed some ubiquitous markers ( HIF1A, TNFAIP6 ) that are overexpressed in HE-Fibro cells (Fig 5).…”