Sparcl1, also known as Hevin, is a secreted glycoprotein belonging to the SPARC family of matricellular proteins. It is implicated in the regulation of cell adhesion, migration, and proliferation and is involved in multiple biological processes such as tissue remodeling, embryogenesis, and muscle differentiation [3,7]. It functions through various signaling pathways including TLR4/NF-κB/p65, TNF/NF-κB, and BMP/TGF-β [1,4,7].

Genetic ablation of Sparcl1 in mouse models has revealed its role in several disease conditions. In non-alcoholic steatohepatitis (NASH), genetic knockout of Sparcl1, knockdown in white adipose tissue, and treatment with a neutralizing antibody alleviated diet-induced NASH pathogenesis. Sparcl1 promotes NASH progression by upregulating CCL2 in hepatocytes through the TLR4/NF-κB/p65 signaling pathway [1]. In viral pneumonia, endothelial deletion of Sparcl1 alleviated detrimental lung inflammation, as Sparcl1 drives a shift to a pro-inflammatory "M1-like" macrophage phenotype via TLR4 activation [2]. In neuropathic pain, hevin-null mice showed reduced inflammatory pain and faster recovery from neuropathic pain after nerve injury, suggesting a role for Sparcl1 in maintaining chronic pain [5].

In conclusion, Sparcl1 plays essential roles in regulating cell-matrix interactions, cell functions, and multiple biological processes. Gene knockout mouse models have been crucial in uncovering its role in diseases such as NASH, viral pneumonia, and neuropathic pain, providing potential therapeutic targets for these conditions.

References:

1. Liu, Bin, Xiang, Liping, Ji, Jing, Zheng, Minghua, Lu, Yan. . Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2. In The Journal of clinical investigation, 131, . doi:10.1172/JCI144801. https://pubmed.ncbi.nlm.nih.gov/34651580/

2. Zhao, Gan, Gentile, Maria E, Xue, Lulu, Meyer, Nuala J, Vaughan, Andrew E. 2024. Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. In Nature communications, 15, 4235. doi:10.1038/s41467-024-48589-3. https://pubmed.ncbi.nlm.nih.gov/38762489/

3. Gagliardi, Filippo, Narayanan, Ashwin, Mortini, Pietro. 2016. SPARCL1 a novel player in cancer biology. In Critical reviews in oncology/hematology, 109, 63-68. doi:10.1016/j.critrevonc.2016.11.013. https://pubmed.ncbi.nlm.nih.gov/28010899/

4. Miao, Yu, Wu, Shenghui, Gong, Ziling, Feng, Yong, Li, Guangyi. 2024. SPARCL1 promotes chondrocytes extracellular matrix degradation and inflammation in osteoarthritis via TNF/NF-κB pathway. In Journal of orthopaedic translation, 46, 116-128. doi:10.1016/j.jot.2024.02.009. https://pubmed.ncbi.nlm.nih.gov/38867741/

5. Chen, Gang, Xu, Jing, Luo, Hao, Eroglu, Cagla, Ji, Ru-Rong. 2022. Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling. In JCI insight, 7, . doi:10.1172/jci.insight.161028. https://pubmed.ncbi.nlm.nih.gov/36256481/

6. Zhao, Gan, Gentile, Maria E, Xue, Lulu, Meyer, Nuala J, Vaughan, Andrew E. 2023. Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.05.25.541966. https://pubmed.ncbi.nlm.nih.gov/37292817/

7. Wang, YuXin, Liu, ShuaiYu, Yan, YunQin, Li, ShuFeng, Tong, HuiLi. 2019. SPARCL1 promotes C2C12 cell differentiation via BMP7-mediated BMP/TGF-β cell signaling pathway. In Cell death & disease, 10, 852. doi:10.1038/s41419-019-2049-4. https://pubmed.ncbi.nlm.nih.gov/31699966/