title: Enhanced immune response to MMP3 stimulation in microglia expressing mutant huntingtin.
abstract: 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.
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Connolly
authors.affiliation: Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 84 Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Magnusson-Lind
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: P K
authors.initials: PK
authors.lastname: Wagner
authors.affiliation: 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.
authors.forename: A L
authors.initials: AL
authors.lastname: Southwell
authors.affiliation: 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.
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, S-221 84 Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Björkqvist
authors.affiliation: 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.
authors.forename: B R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D061251:Primary Cell Culture
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C577686:interleukin-6, mouse; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Huntington’s Disease; MMP3; microglia; neuroinflammation