2. Academic Validation
  3. Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides

Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides

  • Brain Behav Immun. 2024 Sep 24:123:315-333. doi: 10.1016/j.bbi.2024.09.027.
Josephine Louise Robb 1,  Frédérick Boisjoly 2,  Arturo Israel Machuca-Parra 1,  Adeline Coursan 3,  Romane Manceau 2,  Danie Majeur 2,  Demetra Rodaros 4,  Khalil Bouyakdan 4,  Karine Greffard 5,  Jean-François Bilodeau 6,  Anik Forest 7,  Caroline Daneault 7,  Matthieu Ruiz 8,  Cyril Laurent 2,  Nathalie Arbour 2,  Sophie Layé 9,  Xavier Fioramonti 9,  Charlotte Madore 9,  Stephanie Fulton 10,  Thierry Alquier 11,  Representative of consortium
Affiliations

Affiliations

  • 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: thierry.alquier@umontreal.ca.
PMID: 39326768 DOI: 10.1016/j.bbi.2024.09.027
Abstract

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.

Keywords

Adipose triglyceride lipase; Interleukin-6; Lipid droplet; Microglia; Neuroinflammation.

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