Dataset Information

Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by the injury of steatotic hepatocytes, triggering the release of endogenous danger-associated molecular patterns (DAMP). The nature of the danger signals and their role in engaging the innate immune cells like macrophage remain to be fully delineated. Recent work demonstrated that exposed lipid droplets (LD) serve as a disease-associated danger signal that promotes monocyte infiltration and its maturation into TREM2+ macrophages within the MASH liver. In this study, we explored the nature of LD-mediated danger signaling and its impact on inflammatory signaling in macrophages. We found that efferocytosis of LDs triggers a global transcriptional response and dampens pro-inflammatory signaling in cultured macrophages. LD treatments attenuated proinflammatory signaling and NLRP3 inflammasome activation via mechanisms independent of lipid hydrolysis by macrophages. TREM2 is required for the attenuation of inflammatory response, whereas MS4A7 downregulation contributes to the dampening effects of LD treatments. These results underscore the dual role of LD-mediating danger signaling in MASH liver by promoting monocyte infiltration and TREM2+ macrophage induction and dampening pro-inflammatory response in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE267716 | GEO | 2025/04/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.

Project description:Background: Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages into the liver. Methods: The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type (WT) controls. MASH was established by feeding mice a high-fat, fructose, and -cholesterol (FFC) diet for 24 weeks which leads to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in FFC-fed S1pr1MKO compared to WT. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of FFC-fed S1pr1MKO mice compared to WT. Gene ontology pathway analysis revealed a significant suppression of the peroxisome proliferator-activated receptor gamma (PPARγ) and mitogen activated protein kinase (MAPK) pathways in S1pr1MKO consistent with attenuated MASH in mice. Conclusion: Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

Dataset Information

Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets