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Published on: March 24, 2023
Liver Sinusoidal Endothelial Cells Promote Metabolic Dysfunction-associated Steatohepatitis Progression via
Kenji Fukumoto1, Hayato Hikita1, Yoshinobu Saito1
1Department of Gastroenterology and Hepatology, The University of Osaka Graduate School of Medicine, Osaka, Japan.
Background & Aims:
Interleukin (IL)-1β is a key cytokine in hepatitis-related inflammation, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) remains unclear. This study investigated IL-1β-mediated interactions in nonparenchymal liver cells to elucidate their contributions to pathological MASH progression.
Methods:
We used the THP-1 monocyte-derived macrophage line and TMNK-1 liver sinusoidal endothelial cell (LSEC) line for in vitro assays. Endothelial cell-specific Il1r1-knockout (Il1r1ΔEC) and systemic Cxcl10-knockout (Cxcl10-/-) mice were subjected to a Western diet (WD) to establish a MASH model. An additional WD-fed cohort received the IL1R1 antagonist anakinra during the final 4 weeks. RNA sequencing data from liver tissues from patients with MASLD and spatial transcriptomic analyses focusing on nontumor regions of MASH-related hepatocellular carcinoma samples were evaluated.
Results:
Liver levels of mature IL-1β were elevated in WD-fed mice compared with ND-fed mice. Il1r1 was highly expressed in LSECs, and Ccl2 and Cxcl10 expression were upregulated in LSECs under WD conditions. Palmitic acid inhibited autophagy in THP-1 macrophages, increasing IL-1β secretion. IL-1β enhanced CCL2 and CXCL10 expression in TMNK-1 LSECs via JNK activation. In Il1r1ΔEC and Cxcl10-/- mice, WD-induced inflammatory cell infiltration and fibrosis were attenuated, and anakinra produced similar effects. In human datasets, CCL2 and CXCL10 were upregulated in MASH livers and correlated with NAFLD activity scores. Spatial transcriptomics revealed a dominant periportal macrophage-to-LSEC IL1B-IL1R1 interaction that generates chemokine-enriched LSECs, forming inflammatory-fibrotic niches that facilitate immune cell recruitment.
Conclusions:
Macrophage-derived IL-1β promotes hepatic inflammation and fibrosis through IL1R1-dependent chemokine induction in LSECs, highlighting IL1R1 signaling as a therapeutic target in MASH.
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