PXD029342

PXD029342 is an original dataset announced via ProteomeXchange.

Title	Plasma proteomics in Stabilin-1 and Stabilin-2 knock-out mice
Description	Scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may impact atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. Methods: ApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet (WD). For antibody targeting, Ldlr-KO mice were also used. Plasma proteomics were performed in Stabilin-deficient mice and candidates were independently confirmed. Ligand binding studies comprised GST-pull down and endocytosis assays. Plasma proteome effects on monocytes were studied by single cell RNA sequencing in vivo, and by gene expression analyses of Stabilin-ligand-stimulated and plasma-stimulated bone marrow-derived monocytes/macrophages in vitro. Results: Spontaneous and WD-associated atherogenesis was significantly reduced in ApoE-Stab1- and ApoE-Stab2-KO. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies significantly reduced WD-associated atherosclerosis in ApoE-KO and Ldlr-KO. While neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing Wildtype with Stab1/2 single and Stab1/2-double KO, and of 43 proteins comparing ApoE-, ApoE-Stab1- and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate scavenger receptor ligands, Periostin, Reelin and TGFBi, known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. scRNA-Seq of circulating myeloid cells of ApoE-, ApoE-Stab1- and ApoE-Stab2-KO showed transcriptomic alterations in patrolling (Ccr2-/Cx3cr1++/Ly6Clo) and inflammatory (Ccr2+/Cx3cr1+/Ly6Chi) monocytes including downregulation of pro-atherogenic transcription factor Egr1. Ligand exposure did not alter Egr1 expression in vitro, but exposure of Wildtype bone marrow-derived monocytes/macrophages to plasma from ApoE-Stab1- and ApoE-Stab2-KO mice showed a reverted pro-atherogenic macrophage activation as compared to ApoE-KO plasma including downregulation of Egr1. Conclusions: Inhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome which includes direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory macrophages and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1- and anti-Stab2-targeted therapies provide a novel approach for the future treatment of atherosclerosis.
HostingRepository	PRIDE
AnnounceDate	2025-01-21
AnnouncementXML	Submission_2025-01-21_03:19:37.693.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hendrik Nolte
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-25 06:49:03	ID requested
⏵ 1	2025-01-21 03:19:38	announced

Manta CP, Leibing T, Friedrich M, Nolte H, Adrian M, Schledzewski K, Krzistetzko J, Kirkamm C, David Schmid C, Xi Y, Stojanovic A, Tonack S, de la Torre C, Hammad S, Offermanns S, Kr, ü, ger M, Cerwenka A, Platten M, Goerdt S, G, é, raud C, Targeting of Scavenger Receptors Stabilin-1 and Stabilin-2 Ameliorates Atherosclerosis by a Plasma Proteome Switch Mediating Monocyte/Macrophage Suppression. Circulation, 146(23):1783-1799(2022) [pubmed]

10.1161/circulationaha.121.058615;

submitter keyword: ApoE, Plasma,Stabilin, LC-MS/MS

Marcus Krüger
contact affiliation	CECAD and Institute for Genetics Joseph-Stelzmann Straße 26 University of Cologne, Cologne, Germany
contact email	marcus.krueger@uni-koeln.de
lab head
Hendrik Nolte
contact affiliation	Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)
contact email	h.nolte@uni-koeln.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/01/PXD029342

PRIDE project URI

• PRIDE
  1. PXD029342
     1. Label: PRIDE project
     2. Name: Plasma proteomics in Stabilin-1 and Stabilin-2 knock-out mice