Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation

Ali Tawbeh (1) , Quentin Raas (1) , Mounia Tahri-Joutey (1, 2) , Céline Keime (3) , Romain Kaiser (3) , Doriane Trompier (1) , Boubker Nasser (2) , Emma Bellanger (4) , Marie Dessard (4) , Yannick Hamon (4) , Alexandre Benani (5, 6) , Francesca Di Cara (7) , Tânia Cunha Alves (8) , Johannes Berger (8) , Isabelle Weinhofer (8) , Stéphane Mandard (9, 10) , Mustapha Cherkaoui-Malki (1) , Pierre Andreoletti (1) , Catherine Gondcaille (1) , Stéphane Savary (1)

1 BIO-PEROXIL - Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon]
2 Faculty of Science and Technology, University Hassan I
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CIML - Centre d'Immunologie de Marseille - Luminy
5 CSGA - Centre des Sciences du Goût et de l'Alimentation [Dijon]
6 UBFC - Université Bourgogne Franche-Comté [COMUE]
7 Dalhousie University [Halifax]
8 Medizinische Universität Wien = Medical University of Vienna
9 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
10 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer

Microglia are crucial for brain homeostasis, and dysfunction of these cells is a key driver in most neurodegenerative diseases, including peroxisomal leukodystrophies. In X-linked adrenoleukodystrophy (X-ALD), a neuroinflammatory disorder, very long-chain fatty acid (VLCFA) accumulation due to impaired degradation within peroxisomes results in microglial defects, but the underlying mechanisms remain unclear. Using CRISPR/Cas9 gene editing of key genes in peroxisomal VLCFA breakdown (Abcd1, Abcd2, and Acox1), we recently established easily accessible microglial BV-2 cell models to study the impact of dysfunctional peroxisomal β-oxidation and revealed a disease-associated microglial-like signature in these cell lines. Transcriptomic analysis suggested consequences on the immune response. To clarify how impaired lipid degradation impacts the immune function of microglia, we here used RNA-sequencing and functional assays related to the immune response to compare wild-type and mutant BV-2 cell lines under basal conditions and upon pro-inflammatory lipopolysaccharide (LPS) activation. A majority of genes encoding proinflammatory cytokines, as well as genes involved in phagocytosis, antigen presentation, and co-stimulation of T lymphocytes, were found differentially overexpressed. The transcriptomic alterations were reflected by altered phagocytic capacity, inflammasome activation, increased release of inflammatory cytokines, including TNF, and upregulated response of T lymphocytes primed by mutant BV-2 cells presenting peptides. Together, the present study shows that peroxisomal β-oxidation defects resulting in lipid alterations, including VLCFA accumulation, directly reprogram the main cellular functions of microglia. The elucidation of this link between lipid metabolism and the immune response of microglia will help to better understand the pathogenesis of peroxisomal leukodystrophies.

Mots clés: adrenoleukodystrophy, antigen presentation, immune response, inflammation, microglia, peroxisome, phagocytosis

Domaines: Biochimie, Biologie Moléculaire; Neurosciences

Ali Tawbeh, Quentin Raas, Mounia Tahri-Joutey, Céline Keime, Romain Kaiser, et al.. Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation. Frontiers in Molecular Neuroscience, 2023, 16, pp.1299314. ⟨10.3389/fnmol.2023.1299314⟩. ⟨hal-04352894⟩