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International Session（Symposium）3(JSGE・JSH・JSGS・JSGCS)
Fri. November 1st   9:30 - 11:30   Room 4: Portopia Hotel South Wing Portopia Hall
IS-S3-6_H
 Elucidation of mechanisms underlying MASH progression through cell-cell interactions in the hepatic microenvironment
Kenji Fukumoto1, Hayato Hikita1, Tetsuo Takehara1
1Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
[Objective] The objective was to elucidate the mechanism of MASH progression through cell-cell interactions starting with liver macrophages.
[Methods and Results] Liver macrophages from MASH mice induced by Western diet (WD) administration, as well as THP-1 macrophages loaded with palmitic acid, exhibited increased secretion of IL-1Β due to autophagy impairment. Analysis of single-cell RNA sequencing of liver tissues and MACS-isolated cells revealed upregulation of inflammatory chemokine gene expression, such as CXCL10 and CCL2, in LSECs of the WD group. IL-1Β in the culture supernatant of THP-1 macrophages activated JNK, thereby enhancing the expression of inflammatory chemokines in LSEC cell line TMNK-1. In the liver hepatitis model induced by intraperitoneal injection of LPS, bone marrow-specific Atg7 KO mice exhibited increased expression of inflammatory chemokines in LSECs compared to wild-type mice. Endothelial cell-specific IL1R1 KO and systemic CXCL10 KO in the MASH model resulted in decreased expression of inflammatory chemokines and monocyte-macrophage-related genes in liver tissues, leading to improved hepatic damage and fibrosis. RNA sequencing of liver biopsy samples from 98 MASLD / MASH patients showed that CXCL10 gene expression increased with the rise in NAS score and exhibited a strong positive correlation with IL1B.
[Conclusion] The increased IL-1Β secretion from hepatic macrophages due to autophagy impairment suggests its potential contribution to the progression of MASH through chemokine induction in LSECs.
Index Term 1: MASH
Index Term 2: Macrophage
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