Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism.

CSF1R LDLR PLX5622 blood-brain barrier cholesterol endothelial cells genetic microglial depletion microglia off-target effects vasculature

Journal

Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320

Informations de publication

Date de publication:
08 Aug 2024
Historique:
received: 07 11 2022
revised: 03 05 2024
accepted: 21 07 2024
medline: 15 8 2024
pubmed: 15 8 2024
entrez: 14 8 2024
Statut: aheadofprint

Résumé

Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.

Identifiants

DOI: 10.1016/j.neuron.2024.07.015 PMID: 39142282
pubmed: 39142282
pii: S0896-6273(24)00537-3
doi: 10.1016/j.neuron.2024.07.015
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Caterina P Profaci (CP)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA. Electronic address: cprofaci@scripps.edu.

Sean S Harvey (SS)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.

Kaja Bajc (K)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.

Tony Z Zhang (TZ)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.

Danielle A Jeffrey (DA)

Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Alexander Z Zhang (AZ)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.

Kelsey M Nemec (KM)

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Hayk Davtyan (H)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Carleigh A O'Brien (CA)

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Gabriel L McKinsey (GL)

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Aaron Longworth (A)

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.

Timothy P McMullen (TP)

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.

Joia K Capocchi (JK)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.

Jessica G Gonzalez (JG)

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.

Devon A Lawson (DA)

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.

Thomas D Arnold (TD)

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Dimitrios Davalos (D)

Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.

Mathew Blurton-Jones (M)

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.

Fabrice Dabertrand (F)

Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

F Chris Bennett (FC)

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Richard Daneman (R)

Department of Pharmacology, University of California, San Diego, La Jolla, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, San Diego, CA, USA.

Classifications MeSH