title: Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency.
abstract: The functional diversity and molecular adaptations of reactive microglia in the chronically inflamed central nervous system (CNS) are poorly understood. We previously showed that mice lacking multifunctional protein 2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, persistently accumulate reactive myeloid cells in the gray matter of the CNS. Here, we show that the increased numbers of myeloid cells solely derive from the proliferation of resident microglia and not from infiltrating monocytes. We defined the signature of Mfp2(-/-) microglia by gene expression profiling after acute isolation, which was validated by quantitative polymerase reaction (qPCR), immunohistochemical, and flow cytometric analysis. The features of Mfp2(-/-) microglia were compared with those from SOD1(G93A) mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of SOD1(G93A) spinal cord, neurons were intact in Mfp2(-/-) brain and Mfp2(-/-) microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of Mfp2(-/-) microglia was accompanied by the downregulation of markers that specify the unique microglial signature in homeostatic conditions. In contrast, mammalian target of rapamycin (mTOR) and downstream glycolytic and protein translation pathways were induced, indicative of metabolic adaptations. Mfp2(-/-) microglia were immunologically activated but not polarized to a pro- or anti-inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in Mfp2(-/-) brain, consistent with a primed state. Taken together, we demonstrate that chronic activation of resident microglia does not necessarily lead to phagocytosis nor overt neurotoxicity.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Cell Metabolism, Leuven, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Verheijden
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Cell Metabolism, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Beckers
authors.affiliation: Department of Oncology, Laboratory of Molecular Oncology and Angiogenesis, KU Leuven-University of Leuven, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, VIB, Vesalius Research Center, Leuven, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Oleg
authors.initials: O
authors.lastname: Butovsky
authors.affiliation: Department of Oncology, Laboratory of Molecular Oncology and Angiogenesis, KU Leuven-University of Leuven, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, VIB, Vesalius Research Center, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Cell Metabolism, Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
mesh_terms: D017398:Alternative Splicing; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006706:Homeostasis / Q000502:physiology; D008070:Lipopolysaccharides; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D064029:Peroxisomal Multifunctional Protein-2 / Q000172:deficiency* / Q000235:genetics; D010587:Phagocytosis / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C491288:Hsd17b4 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D064029:Peroxisomal Multifunctional Protein-2
keywords: mTOR; microglia; multifunctional protein 2; neuroinflammation; peroxisomes; phagocytosis
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