Identification of a chronic non‐neurodegenerative microglia activation state in a mouse model of peroxisomal β‐oxidation deficiency. Issue 9 (2nd April 2015)

• Record Type: Journal Article
• Authors: Verheijden, Simon; Beckers, Lien; Casazza, Andrea; Butovsky, Oleg; Mazzone, Massimiliano; Baes, Myriam
• Is Part Of: Glia. Volume 63:Issue 9(2015:Sep.)
• Page Start: 1606
• Page End: 1620
• Publication Date: 2015-04-02
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22831
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>Mfp2</italic><sup>−/−</sup> microglia by gene expression profiling after acute isolation, which was validated by quantitative polymerase reaction (qPCR), immunohistochemical, and flow cytometric analysis. The features of <italic>Mfp2</italic><sup>−/−</sup> microglia were compared with those from <italic>SOD1</italic><sup>G93A</sup> mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of <italic>SOD1</italic><sup>G93A</sup> spinal cord, neurons were intact in <italic>Mfp2</italic><sup>−/−</sup> brain and <italic>Mfp2</italic><sup>−/−</sup> microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of <italic>Mfp2</italic><sup>−/−</sup> 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. <italic>Mfp2</italic><sup>−/−</sup> microglia were immunologically activated but not polarized to a pro‐ or anti‐inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in <italic>Mfp2</italic><sup>−/−</sup> 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. GLIA 2015;63:1606–1620</p> </abstract>