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Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Konrad Hoeft1, Gideon J L Schaefer1, Hyojin Kim2

  • 1Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.

Cell Reports
|February 22, 2023
PubMed

Insights

Researchers identified specific profibrotic macrophages (Spp1 macrophages) that drive organ fibrosis. Targeting chemokine ligand 4 (CXCL4) and these macrophages may offer new therapeutic strategies for fibrotic diseases.

Area of Science:

  • Immunology
  • Pathology
  • Molecular Biology

Background:

  • Fibrosis is a common endpoint of chronic organ damage, leading to tissue destruction and organ failure.
  • Profibrotic macrophages play a critical role in the development and progression of fibrosis.
  • Understanding the molecular mechanisms driving macrophage activation in fibrosis is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify and characterize novel cell populations involved in profibrotic processes.
  • To elucidate the role of specific molecular mediators in macrophage-driven fibrosis.
  • To explore potential therapeutic targets for mitigating organ fibrosis.

Main Methods:

  • Unbiased gene expression profiling to identify markers of profibrotic macrophages.
  • In vitro and in vivo models of heart and kidney injury.
  • Genetic manipulation to assess the function of identified genes and cell populations.
  • Single nuclear RNA sequencing and ligand-receptor interaction analysis.

Main Results:

  • A distinct population of profibrotic macrophages, expressing Spp1, Fn1, and Arg1 (Spp1 macrophages), was identified and found to expand after organ injury.
  • Chemokine (C-X-C motif) ligand 4 (CXCL4) was identified as a key upregulated gene during Spp1 macrophage differentiation.
  • Loss of CXCL4 inhibited Spp1 macrophage differentiation and reduced fibrosis in cardiac and renal injury models.
  • Platelets were identified as a major source of CXCL4, driving Spp1 macrophage differentiation.
  • Macrophages orchestrate fibroblast activation through Spp1, Fn1, and Sema3 signaling pathways.
  • Spp1 macrophages were found to be expanded in human chronic kidney disease and heart failure.

Conclusions:

  • Spp1 macrophages represent a key cellular driver of organ fibrosis.
  • CXCL4, primarily sourced from platelets, is essential for Spp1 macrophage differentiation and subsequent fibrosis.
  • Targeting the CXCL4-Spp1 macrophage axis offers a promising therapeutic strategy for fibrotic diseases.
  • Spp1 macrophages are relevant in human fibrotic conditions, including chronic kidney disease and heart failure.
Keywords:
CP: ImmunologyCXCL4PF4SPP1SPP1 macrophageschronic kidney diseasefibrosisheart failureinnate immunitymyocardial infarctionplatelets

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