Inhibition of Chitinase-3-like-1 expression by K284 ameliorates lipopolysaccharide-induced acute liver injury through down regulation of CXCL3

• Published in: International immunopharmacology 2023-03, Vol.116, p.109877, Article 109877
• Main Authors: Kim, Minji, Yeo, In Jun, Son, Dong Ju, Lee, Heepom, Yun, Jaesuk, Han, Sang-Bae, Hong, Jin Tae
• Format: Article
• Language: English
• Subjects: CHIL31; CXCL3; K284; M2 polarization cytokine; Sepsis liver
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.109877

•K284 alleviated sepsis by controlling the expression of CHI3L1.•K284 downgrades the expression of M2 polarization.•K284 influenced the regulation of expression of CXCL3.•K284 downgraded M2 polarization expression through the regulation of expression of CXCL3 related to CHI3L1, thereby alleviating sepsis. Chitinase 3 like 1 protein (CHI3L1) is involved in various types of infectious disease, especially sepsis. Aberrant expression of CHI3L1 could play a critical role in inflammation and immune responses. Previously, we found that compound K284 has the highest binding activity to CHI3L1. In this study, we investigated the effect of K284 on liver injury during sepsis using a lipopolysaccharide (LPS)-induced C57BL/6 mouse model. We found that the survival rate was a 65 % in LPS + K284 injected mice whereas it was 0% in LPS-treated mice. The serum levels of hepatic injury-related enzymes were decreased in K284-injected mice, indicating that septic liver damage was alleviated by K284. In addition, expression levels of M2 polarization markers were reduced in liver tissues of K284-injected mice. Depletion of CHI3L1 in LPS-treated THLE-2 cells decreased the expression of M2 polarization marker proteins. We investigated the major pathway involved in the observed effects and found that CXCL3 expression is correlated with that of CHI3L1. We found that the expression of CXCL3 was lowered in liver tissues of LPS + K284-treated mice compared with LPS-treated mice. M2 polarization-related cytokine levels were increased by the combination of LPS and recombinant CXCL3, but decreased by K284. M2 polarization-related cytokines, CHI3L1 and CXCL3 expression levels were decreased by CXCL3 siRNA, and further decreased by combination treatment of CXCL3 siRNA and K284. Therefore, CXCL3 might be a significant chemokine involved in the reduction of LPS-induced liver injury during sepsis by K284. Our findings indicate that K284 could be a suitable treatment for sepsis like hepatic injury.