PMID- 27033979
OWN - NLM
STAT- MEDLINE
DCOM- 20170607
LR  - 20171102
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 325
DP  - 2016 Jun 14
TI  - Enhanced immune response to MMP3 stimulation in microglia expressing mutant 
      huntingtin.
PG  - 74-88
LID - S0306-4522(16)30001-X [pii]
LID - 10.1016/j.neuroscience.2016.03.031 [doi]
AB  - Huntington's Disease (HD) is an inherited neurodegenerative disease caused by a 
      polyglutamine expansion in the huntingtin protein. The YAC128 mouse model of HD 
      expresses the full-length human huntingtin protein with 128 CAG repeats and 
      replicates the phenotype and neurodegeneration that occur in HD. Several studies 
      have implicated a role for neuroinflammation in HD pathogenesis. Studies on 
      presymptomatic HD patients have illustrated microgliosis (activated microglia) in 
      brain regions affected in HD. Mutant huntingtin expressing isolated primary 
      monocytes (human HD patients) and primary macrophages (YAC128) are overactive in 
      response to lipopolysaccharide (LPS) stimulation. In this study we demonstrate 
      that cultured primary microglia (the resident immune cells of the brain cells) 
      from YAC128 mice differentially express a wide number of cytokines compared to 
      wildtype microglia cultures in response to LPS. Furthermore, this study outlines 
      a direct interaction between mutant huntingtin and cytokine secretion in HD 
      microglia. Increased cytokine release in YAC128 microglia can be blocked by 
      cannabinoid activation or by mutant huntingtin knockdown with anti-sense 
      oligonucleotide treatment. Matrix metalloprotease 3 (MMP3), an endogenous 
      neuronal activator of microglia, also induces increased cytokine release from 
      YAC128 microglia compared to wildtype microglia. We found elevated MMP levels in 
      HD CSF, and MMP levels correlate with disease severity in HD. These data support 
      a novel role for MMPs and microglial activation in HD pathogenesis. With an 
      improved understanding of the specific cellular processes involved in HD 
      neuroinflammation, novel therapeutic agents targeting these processes can be 
      developed and hold great promise in the treatment of HD.
CI  - Copyright (c) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Connolly, C
AU  - Connolly C
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada.
FAU - Magnusson-Lind, A
AU  - Magnusson-Lind A
AD  - Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, 
      Wallenberg Neuroscience Center, Lund University, S-221 84 Lund, Sweden.
FAU - Lu, G
AU  - Lu G
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada.
FAU - Wagner, P K
AU  - Wagner PK
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada.
FAU - Southwell, A L
AU  - Southwell AL
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada.
FAU - Hayden, M R
AU  - Hayden MR
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada.
FAU - Bjorkqvist, M
AU  - Bjorkqvist M
AD  - Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, 
      Wallenberg Neuroscience Center, Lund University, S-221 84 Lund, Sweden.
FAU - Leavitt, B R
AU  - Leavitt BR
AD  - Centre for Molecular Medicine and Therapeutics and Department of Medical 
      Genetics, Child and Family Research Institute, University of British Columbia, 
      Vancouver, BC V5Z 4H4, Canada. Electronic address: bleavitt@cmmt.ubc.ca.
LA  - eng
PT  - Journal Article
DEP - 20160323
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (interleukin-6, mouse)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Encephalitis/chemically induced/*immunology/metabolism
MH  - Female
MH  - Humans
MH  - Huntingtin Protein/*genetics
MH  - Huntington Disease/*immunology/metabolism
MH  - Inflammation Mediators/metabolism
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides
MH  - Male
MH  - Matrix Metalloproteinase 3/*administration & dosage
MH  - Mice
MH  - Mice, Transgenic
MH  - Microglia/*immunology/metabolism
MH  - Mutation
MH  - Primary Cell Culture
OTO - NOTNLM
OT  - Huntington's Disease
OT  - MMP3
OT  - microglia
OT  - neuroinflammation
EDAT- 2016/04/02 06:00
MHDA- 2017/06/08 06:00
CRDT- 2016/04/02 06:00
PHST- 2015/11/18 00:00 [received]
PHST- 2016/03/09 00:00 [revised]
PHST- 2016/03/11 00:00 [accepted]
PHST- 2016/04/02 06:00 [entrez]
PHST- 2016/04/02 06:00 [pubmed]
PHST- 2017/06/08 06:00 [medline]
AID - S0306-4522(16)30001-X [pii]
AID - 10.1016/j.neuroscience.2016.03.031 [doi]
PST - ppublish
SO  - Neuroscience. 2016 Jun 14;325:74-88. doi: 10.1016/j.neuroscience.2016.03.031. 
      Epub 2016 Mar 23.