PMID- 25846981
OWN - NLM
STAT- MEDLINE
DCOM- 20160413
LR  - 20211203
IS  - 1098-1136 (Electronic)
IS  - 0894-1491 (Print)
IS  - 0894-1491 (Linking)
VI  - 63
IP  - 9
DP  - 2015 Sep
TI  - Identification of a chronic non-neurodegenerative microglia activation state in a 
      mouse model of peroxisomal beta-oxidation deficiency.
PG  - 1606-20
LID - 10.1002/glia.22831 [doi]
AB  - 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 beta-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.
CI  - (c) 2015 Wiley Periodicals, Inc.
FAU - Verheijden, Simon
AU  - Verheijden S
AD  - Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University 
      of Leuven, Cell Metabolism, Leuven, Belgium.
FAU - Beckers, Lien
AU  - Beckers L
AD  - Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University 
      of Leuven, Cell Metabolism, Leuven, Belgium.
FAU - Casazza, Andrea
AU  - Casazza A
AD  - Department of Oncology, Laboratory of Molecular Oncology and Angiogenesis, KU 
      Leuven-University of Leuven, Leuven, Belgium.
AD  - Laboratory of Molecular Oncology and Angiogenesis, VIB, Vesalius Research Center, 
      Leuven, Belgium.
FAU - Butovsky, Oleg
AU  - Butovsky O
AD  - Center for Neurologic Diseases, Department of Neurology, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Mazzone, Massimiliano
AU  - Mazzone M
AD  - Department of Oncology, Laboratory of Molecular Oncology and Angiogenesis, KU 
      Leuven-University of Leuven, Leuven, Belgium.
AD  - Laboratory of Molecular Oncology and Angiogenesis, VIB, Vesalius Research Center, 
      Leuven, Belgium.
FAU - Baes, Myriam
AU  - Baes M
AD  - Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University 
      of Leuven, Cell Metabolism, Leuven, Belgium.
LA  - eng
GR  - R01 NS088137/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150402
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Lipopolysaccharides)
RN  - EC 1.1.1.119 (Hsd17b4 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 4.2.1.107 (Peroxisomal Multifunctional Protein-2)
SB  - IM
MH  - Alternative Splicing
MH  - Amyotrophic Lateral Sclerosis/pathology/physiopathology
MH  - Animals
MH  - Brain/pathology/physiopathology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Homeostasis/physiology
MH  - Lipopolysaccharides
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Microglia/pathology/*physiology
MH  - Neuroimmunomodulation/physiology
MH  - Neurons/pathology/physiology
MH  - Peroxisomal Multifunctional Protein-2/*deficiency/genetics
MH  - Phagocytosis/physiology
MH  - Spinal Cord/pathology/physiopathology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC6572738
MID - NIHMS888003
OTO - NOTNLM
OT  - mTOR
OT  - microglia
OT  - multifunctional protein 2
OT  - neuroinflammation
OT  - peroxisomes
OT  - phagocytosis
EDAT- 2015/04/08 06:00
MHDA- 2016/04/14 06:00
PMCR- 2019/06/17
CRDT- 2015/04/08 06:00
PHST- 2014/11/05 00:00 [received]
PHST- 2015/03/09 00:00 [revised]
PHST- 2015/03/17 00:00 [accepted]
PHST- 2015/04/08 06:00 [entrez]
PHST- 2015/04/08 06:00 [pubmed]
PHST- 2016/04/14 06:00 [medline]
PHST- 2019/06/17 00:00 [pmc-release]
AID - 10.1002/glia.22831 [doi]
PST - ppublish
SO  - Glia. 2015 Sep;63(9):1606-20. doi: 10.1002/glia.22831. Epub 2015 Apr 2.