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

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.

Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

“…LRRK2 mRNA is upregulated in inflamed CD intestinal tissue relative to uninflamed tissue from the same patient, and this LRRK2 expression was localized to macrophages, B cells, and dendritic cells in the lamina propria, a thin layer of connective tissue that lines the intestinal tract 72 . A recent study identified that CD14+ monocytes from the blood of CD patients with the LRRK2 M2397T variant exhibit an elevated pro-inflammatory response to IFNγ relative to healthy controls 75 . Paneth cells are specialized secretory cells in the small intestine that regulate intestinal microbiome and innate immune response.…”

Intestinal Inflammation and Parkinson’s Disease

“…LRRK2 is increased in patients with CD and the increase is possibly induced by interferon-γ (IFN-γ). A recent study has shown an elevated pro-inflammatory response of CD14+ monocytes from CD patients with the LRRK2 M2397 to IFN-γ [ 75 ]. Vice versa, transgenic mice overexpressing LRRK2 have been found exhibited more severe dextran sodium sulfate (DSS)-induced colitis than control animals [ 76 ].…”

Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection

“…By understanding how mitochondrion-triggered innate immune responses influence tuberculosis disease severity, we might one day develop hostdirected therapeutics designed to correct imbalances in these responses and promote positive tuberculosis patient outcomes. Likewise, because mitochondrial mutations that confer susceptibility to mycobacterial infection are also associated with several chronic diseases, including Parkinson's disease (PD) (12)(13)(14)(15), Crohn's disease (16)(17)(18)(19), inflammatory bowel disease (20)(21)(22), and cancer, understanding how they alter mitochondrial function and dysregulate immune responses will help illuminate common molecular mechanisms driving these otherwise disparate diseases.…”