Mutant huntingtin protein alters the response of microglial cells to inflammatory stimuli
| Autor: | Jason P. Gigley, Jonathan H. Fox, Nelson R, David W. Donley |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Microglia Lipopolysaccharide Chemistry medicine.medical_treatment Inflammation Stimulation Cell biology Nitric oxide 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system medicine.anatomical_structure Cytokine medicine Huntingtin Protein medicine.symptom 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/550913 |
| Popis: | Huntington’s disease (HD) is a progressive neurodegenerative disease that affects the striatum and cerebral cortex. It is caused by a dominant CAG trinucleotide expansion in exon 1 of theHTTgene. Mutant huntingtin protein (mHtt) is expressed in neurons and immune cells. HD patients demonstrate altered blood cytokine profiles and altered responses of peripheral immune cells to inflammatory stimuli. However, the effects of mHtt on microglial immune responses are not fully understood. Herein we discuss the current understanding of how mHtt alters microglial inflammatory responses. Using lentivirus, we expressed the N171 N-terminal fragment of wild-type or mhtt containing 18 and 82 glutamine repeats in cultured EOC-20 microglial cells. We then measured responses to lipopolysaccharide or interleukin-6. Mutant huntingtin-expressing microglial cells produced less interleukin-6 and nitric oxide in response to lipopolysaccharide stimulation than wild-type huntingtin-expressing cells. However, mHtt-expressing microglia stimulated with interleukin-6 produced more nitric oxide than wild-type cells. Mutant huntingtin-expressing cells had higher basal NF-κB and further elevations of NF-κB after interleukin-6 but not lipopolysaccharide stimulation. Thus we demonstrate the potential of mHtt to dampen responses to lipopolysaccharide but potentiate responses to interleukin-6. This work adds to the emerging understanding that mHtt alters not only baseline status of cells but may also result in altered immune responses dependent on the nature of the inflammatory stimuli. We also present our perspective that in human HD the extent of inflammation may depend, in part, on altered responses to varied inflammatory stimuli including environmental factors such as infection. |
| Databáze: | OpenAIRE |
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