Crohn's and Parkinson's Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14+ Blood Monocytes Ex Vivo.
J Neuroimmune Pharmacol
; 15(4): 794-800, 2020 12.
Article
en En
| MEDLINE
| ID: mdl-32180132
ABSTRACT
The Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson's disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn's disease (CD). LRRK2 is expressed in human CD14+ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14+ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14+ cells in CD but not in control group. CD14+ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response. Graphical Abstract.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Monocitos
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Enfermedad de Crohn
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Interferón gamma
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Receptores de Lipopolisacáridos
/
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Tipo de estudio:
Risk_factors_studies
Límite:
Adult
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Neuroimmune Pharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
/
NEUROLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos