Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides.
Brain, Behavior, and Immunity. 2025-01-01; 123: 315-333
DOI: 10.1016/j.bbi.2024.09.027
Lire sur PubMed
Robb JL(1), Boisjoly F(2), Machuca-Parra AI(1), Coursan A(3), Manceau R(2), Majeur D(2), Rodaros D(4), Bouyakdan K(4), Greffard K(5), Bilodeau JF(6), Forest A(7), Daneault C(7), Ruiz M(8), Laurent C(2), Arbour N(2), Layé S(9), Fioramonti X(9), Madore C(9), Fulton S(10), Alquier T(11); Representative of consortium.
Author information:
(1)Centre de Recherche du Centre Hospitalier de l’Université de Montréal
(CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada; Département de
Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
(2)Centre de Recherche du Centre Hospitalier de l’Université de Montréal
(CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada; Département de
Neurosciences, Université de Montréal, Montréal, QC H3T 1J4, Canada.
(3)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000
Bordeaux, France.
(4)Centre de Recherche du Centre Hospitalier de l’Université de Montréal
(CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada.
(5)Axe Endocrinologie et Néphrologie, CHU de Québec-Université Laval, Québec, QC
G1V 4G2, Canada.
(6)Axe Endocrinologie et Néphrologie, CHU de Québec-Université Laval, Québec, QC
G1V 4G2, Canada; Département de Médecine, Faculté de Médecine, Université Laval,
Québec, QC, G1K 7P4, Canada.
(7)Institut de Cardiologie de Montréal, Plateforme de métabolomique, Montréal,
QC H1T1C8, Canada.
(8)Département de Nutrition, Université de Montréal, Montréal, QC H3T 1J4,
Canada; Institut de Cardiologie de Montréal, Plateforme de métabolomique,
Montréal, QC H1T1C8, Canada.
(9)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000
Bordeaux, France; Food4BrainHealth France-Canada International Research Network,
Bordeaux, France.
(10)Centre de Recherche du Centre Hospitalier de l’Université de Montréal
(CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada; Département de
Nutrition, Université de Montréal, Montréal, QC H3T 1J4, Canada;
Food4BrainHealth France-Canada International Research Network, Bordeaux, France.
(11)Centre de Recherche du Centre Hospitalier de l’Université de Montréal
(CRCHUM), Université de Montréal, Montréal, QC H3T 1J4, Canada; Département de
Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Food4BrainHealth
France-Canada International Research Network, Bordeaux, France. Electronic
address: .
Lipid droplets (LD) are triglyceride storing organelles that have emerged as an
important component of cellular inflammatory responses. LD lipolysis via adipose
triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of
triglyceride lipolysis, regulates inflammation in peripheral immune and
non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the
periphery in a cell-type dependent manner. The present study determined the
impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function
on acute inflammatory and behavioural responses to pro-inflammatory insult.
First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide
(LPS)-induced expression and secretion of cytokines and phagocytosis in mouse
primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS
led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat
alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL
had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and
adult microglia cultures. CCL2 and IL-6 secretion were also reduced by
ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal
cultures independently from LPS treatment. Second, targeted and untargeted lipid
profiling revealed that ATGListatin reduced LPS-induced generation of
pro-inflammatory prostanoids and modulated ceramide species in neonatal
microglia. Finally, the role of microglial ATGL in neuroinflammation was
assessed using a novel microglia-specific and inducible ATGL knockout mouse
model. Loss of microglial ATGL in adult male mice dampened LPS-induced
expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and
anxiety-like behaviours were also reduced in male mice with loss of ATGL in
microglia. Together, our results demonstrate potent anti-inflammatory effects
produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride
lipolysis and thereby propose that supressing microglial LD lipolysis has
beneficial actions in acute neuroinflammatory conditions.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbi.2024.09.027
PMID: 39326768 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.