Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease.
Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease.
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DOI：
10.1186/s12974-018-1286-2
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发表时间：
2018-08-30
影响因子：
9.3
通讯作者：
Harms AS
中科院分区：
文献类型：
--
作者：
Williams GP;Schonhoff AM;Jurkuvenaite A;Thome AD;Standaert DG;Harms AS
Parkinson’s disease (PD) is characterized by intracellular alpha-synuclein (α-syn) inclusions, progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and activation of the innate and adaptive immune systems. Disruption of immune signaling between the central nervous system (CNS) and periphery, such as through targeting the chemokine receptor type 2 (CCR2) or the major histocompatibility complex II (MHCII), is neuroprotective in rodent models of PD, suggesting a key role for innate and adaptive immunity in disease progression. The purpose of this study was to investigate whether genetic knockout or RNA silencing of the class II transactivator (CIITA), a transcriptional co-activator required for MHCII induction, is effective in reducing the neuroinflammation and neurodegeneration observed in an α-syn mouse model of PD. In vitro, we utilized microglia cultures from WT or CIITA −/− mice treated with α-syn fibrils to investigate inflammatory iNOS expression and antigen processing via immunocytochemistry (ICC). In vivo, an adeno-associated virus (AAV) was used to overexpress α-syn in WT and CIITA −/− mice as a model for PD. Concurrently with AAV-mediated overexpression of α-syn, WT mice received CIITA-targeted shRNAs packaged in lentiviral constructs. Immunohistochemistry and flow cytometry were used to assess inflammation and peripheral cell infiltration at 4 weeks post transduction, and unbiased stereology was used 6 months post transduction to assess neurodegeneration. Using ICC and DQ-ovalbumin, we show that CIITA −/− microglial cultures failed to upregulate iNOS and MHCII expression, and had decreased antigen processing in response to α-syn fibrils when compared to WT microglia. In vivo, global knock-out of CIITA as well as local knockdown using lentiviral shRNAs targeting CIITA attenuated MHCII expression, peripheral immune cell infiltration, and α-syn-induced neurodegeneration. Our data provide evidence that CIITA is required for α-syn-induced MHCII induction and subsequent infiltration of peripheral immune cells in an α-syn mouse model of PD. Additionally, we demonstrate that CIITA in the CNS drives neuroinflammation and neurodegeneration. These data provide further support that the disruption or modulation of antigen processing and presentation via CIITA is a promising target for therapeutic development in preclinical animal models of PD. The online version of this article (10.1186/s12974-018-1286-2) contains supplementary material, which is available to authorized users.
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影响因子：
4.7
作者：
Constantinescu, CS;Tani, M;Rostami, A
通讯作者：
Rostami, A
影响因子：
6.2
作者：
Immig, Kerstin;Gericke, Martin;Bechmann, Ingo
通讯作者：
Bechmann, Ingo
影响因子：
32.4
作者：
Herz J;Filiano AJ;Wiltbank AT;Yogev N;Kipnis J
通讯作者：
Kipnis J
DOI：
10.1523/jneurosci.5601-11.2012
发表时间：
2012-02-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Moehle MS;Webber PJ;Tse T;Sukar N;Standaert DG;DeSilva TM;Cowell RM;West AB
通讯作者：
West AB
影响因子：
3.3
作者：
Laurie, Chad;Reynolds, Ashley;Mosley, R. Lee
通讯作者：
Mosley, R. Lee