Crohn ’s and Parkinson’s Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14 + Blood Monocytes Ex Vivo

AbstractThe Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson ’s disease (PD). The M2397T polymorphism inLRRK2 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 byLRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linkedLRRK2 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 enhancedTNFA, 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 R1441CLRRK2 mutated PD cases and carriers show no changes in IFN- γ responses forTNFA orIL12, reduced response forHLADRA1, and enhanced responses forLRRK2 in FK506-sensitive manner. These data demonstrate that CD-associatedLRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associatedLRRK2 mutation may contribute to reduced antigen presentation response.Graphical Abstract
Source: Journal of NeuroImmune Pharmacology - Category: Drugs & Pharmacology Source Type: research