Chil3, also known as chitinase-like protein 3, is associated with various biological functions. It is an effector downstream of CX3CR1 deficiency and is secreted by M2 macrophages. In the context of liver ischemia-reperfusion (HIR), it plays a role in the recovery of hepatic metabolism [1]. It is also part of an immunoregulatory gene signature in intratumoral monocytes, and its expression is related to outcomes in human tumors [2].

In the liver, M2 macrophage-secreted CHIL3/CHI3L1 improved hepatocellular metabolism and reduced oxygen-glucose deprivation and reoxygenation (OGD/R)-inflicted injuries in cultured mouse and human hepatocytes. Combined treatment with 5-aminolevulinate (5-ALA) and CHIL3 during the ischemic phase facilitated lipid metabolism and ATP production in the mouse liver following HIR [1]. In the tumor microenvironment, the reduction of monocytes expressing Chil3 was associated with tumor regression after intravenous vaccination in mice [2]. In obese mice, glucocorticoids inhibit Chil3 expression in macrophages via KLF9, leading to increased adiposity [3]. In Helicobacter pylori-induced chronic atrophic gastritis, berberine increased Chil3 mRNA expression, promoting M2-polarized macrophages [4]. In sepsis-induced acute lung injury, deletion of Padi2 and Padi4 reduced Nlrp3+ proinflammatory macrophages and fostered Chil3+ myeloid cell differentiation into anti-inflammatory macrophages [5].

In conclusion, Chil3 is involved in the regulation of metabolism, immune response, and cell polarization in different physiological and pathological conditions. Mouse models, such as those with gene-targeted manipulations, have been crucial in revealing its role in liver ischemia-reperfusion injury, tumor immunotherapy, obesity-related inflammation, chronic atrophic gastritis, and sepsis-induced acute lung injury. These findings enhance our understanding of biological processes and potential therapeutic targets related to these disease areas.

References:

1. Jin, Guanghui, Guo, Na, Liu, Yasong, Yang, Yang, Ou, Jingxing. 2023. 5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury. In Theranostics, 13, 4802-4820. doi:10.7150/thno.83163. https://pubmed.ncbi.nlm.nih.gov/37771779/

2. Baharom, Faezzah, Ramirez-Valdez, Ramiro A, Khalilnezhad, Ahad, Ishizuka, Andrew S, Seder, Robert A. 2022. Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment. In Cell, 185, 4317-4332.e15. doi:10.1016/j.cell.2022.10.006. https://pubmed.ncbi.nlm.nih.gov/36302380/

3. Zhang, Yinliang, Du, Chunyuan, Wang, Wei, Chen, Shihong, Chang, Yongsheng. 2024. Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages. In Nature communications, 15, 1190. doi:10.1038/s41467-024-45477-8. https://pubmed.ncbi.nlm.nih.gov/38331933/

4. Yang, Tao, Wang, Ruilin, Liu, Honghong, Yang, Xiangdong, Zhao, Yanling. 2020. Berberine regulates macrophage polarization through IL-4-STAT6 signaling pathway in Helicobacter pylori-induced chronic atrophic gastritis. In Life sciences, 266, 118903. doi:10.1016/j.lfs.2020.118903. https://pubmed.ncbi.nlm.nih.gov/33340526/

5. Yu, Xin, Song, Yujing, Dong, Tao, Ma, Jianjie, Li, Yongqing. 2024. Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages. In JCI insight, 9, . doi:10.1172/jci.insight.181686. https://pubmed.ncbi.nlm.nih.gov/39405117/