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Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease.
J Neuroinflammation. 2018 Aug 30; 15(1):244.JN

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Authors+Show Affiliations

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 525, Birmingham, AL, 35294-0021, USA.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 525, Birmingham, AL, 35294-0021, USA.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 525, Birmingham, AL, 35294-0021, USA.Department of Neurology, Houston Methodist Hospital, Houston, TX, 77030, USA.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 525, Birmingham, AL, 35294-0021, USA.Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 525, Birmingham, AL, 35294-0021, USA. anharms@uab.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30165873

Citation

Williams, Gregory P., et al. "Targeting of the Class II Transactivator Attenuates Inflammation and Neurodegeneration in an Alpha-synuclein Model of Parkinson's Disease." Journal of Neuroinflammation, vol. 15, no. 1, 2018, p. 244.
Williams GP, Schonhoff AM, Jurkuvenaite A, et al. Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease. J Neuroinflammation. 2018;15(1):244.
Williams, G. P., Schonhoff, A. M., Jurkuvenaite, A., Thome, A. D., Standaert, D. G., & Harms, A. S. (2018). Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease. Journal of Neuroinflammation, 15(1), 244. https://doi.org/10.1186/s12974-018-1286-2
Williams GP, et al. Targeting of the Class II Transactivator Attenuates Inflammation and Neurodegeneration in an Alpha-synuclein Model of Parkinson's Disease. J Neuroinflammation. 2018 Aug 30;15(1):244. PubMed PMID: 30165873.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease. AU - Williams,Gregory P, AU - Schonhoff,Aubrey M, AU - Jurkuvenaite,Asta, AU - Thome,Aaron D, AU - Standaert,David G, AU - Harms,Ashley S, Y1 - 2018/08/30/ PY - 2018/05/30/received PY - 2018/08/20/accepted PY - 2018/9/1/entrez PY - 2018/9/1/pubmed PY - 2018/11/27/medline KW - Class II transactivator (CIITA) KW - Major histocompatibility complex II (MHCII) KW - Microglia KW - Monocytes KW - Neurodegeneration KW - Neuroinflammation KW - Parkinson’s disease (PD) KW - T cells KW - α-Synuclein SP - 244 EP - 244 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 15 IS - 1 N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/30165873/Targeting_of_the_class_II_transactivator_attenuates_inflammation_and_neurodegeneration_in_an_alpha_synuclein_model_of_Parkinson's_disease_ DB - PRIME DP - Unbound Medicine ER -