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Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
MIF-mediated crosstalk between THRSP + hepatocytes and CD74 + lipid-associated macrophages in hepatic periportal zone
Xu Xu1,2, Huagen Li3, Hai Lin4
1Department of Otolaryngology Head and Neck Surgery, Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background And Aims:
Spatial location of steatosis is closely related to the progression of metabolic dysfunction-associated steatohepatitis (MASH), and reports suggest lipid-associated macrophages (LAMs) facilitate this progression. However, the underlying mechanisms remain elusive.
Approach And Results:
Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in the hepatic periportal (PP) zone of MASH mice, suggesting a vital role of the PP zone in MASH progression. THRSP (SPOT14), involved in fatty acid synthesis, was markedly elevated in the livers of MASH patients and mice. Notably, CellPhoneDB analysis identified strong interactions between CD74 and macrophage migration inhibitory factor (MIF) within the Thrsp -high zone. Furthermore, Thrsp , Cd74 , Mif , Col3a1 , and LAMs markers were prominently colocalized in the hepatic PP zone of MASH mice, suggesting that Thrsp -mediated crosstalk in this region played a crucial role in MASH progression. Thrsp overexpression/knockout experiments confirmed that THRSP drove MASH progression by recruiting CD74 + LAMs mediated by MIF. Mechanistically, THRSP promoted hepatic palmitic acid (PA) synthesis, mainly by promoting hepatic de novo lipogenesis, and disturbing the binding of FASN-TRIM21, thereby inhibiting FASN ubiquitination. CD74 + LAMs were activated and recruited by chemokine-like MIF secreted from hepatocytes and macrophages stimulated with PA. Additionally, the compound C6, identified as a THRSP inhibitor, significantly ameliorated MASH in mice.
Conclusions:
Our study demonstrates that THRSP drives MASH progression by recruiting CD74 + LAMs mediated by MIF in the hepatic PP zone, providing novel insights into the spatial zonation and crosstalk between lipogenic hepatocytes and LAMs that may result in novel therapies for MASH.
Insights
THRSP drives MASH progression by recruiting CD74+ lipid-associated macrophages (LAMs) via MIF in the hepatic periportal zone. A THRSP inhibitor, C6, ameliorated MASH in mice, suggesting new therapeutic strategies.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Steatosis spatial zonation impacts MASH progression.
- Lipid-associated macrophages (LAMs) are implicated in MASH.
- Mechanisms linking steatosis, LAMs, and MASH remain unclear.
Purpose of the Study:
- Investigate the role of THRSP in MASH progression.
- Elucidate the spatial mechanisms of MASH development.
- Identify potential therapeutic targets for MASH.
Main Methods:
- Spatial transcriptomics (ST) analysis in MASH mouse models.
- CellPhoneDB for cell-cell interaction analysis.
- Thrsp overexpression/knockout and pharmacological inhibition (C6).
Main Results:
- THRSP and MASH genes are elevated in the hepatic periportal (PP) zone.
- THRSP promotes MASH by recruiting CD74+ LAMs via MIF.
- THRSP enhances palmitic acid synthesis and inhibits FASN ubiquitination.
- THRSP inhibition with C6 ameliorated MASH in mice.
Conclusions:
- THRSP drives MASH progression via PP zone crosstalk between hepatocytes and LAMs.
- MIF mediates the recruitment of CD74+ LAMs by THRSP-expressing hepatocytes.
- THRSP inhibition presents a potential therapeutic avenue for MASH.
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