An increase in LRRK2 suppresses autophagy and enhances Dectin-1–induced immunity in a mouse model of colitis

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Science Translational Medicine  06 Jun 2018:
Vol. 10, Issue 444, eaan8162
DOI: 10.1126/scitranslmed.aan8162

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  • RE: An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis
    • Dianne Sika-Paotonu, Associate Dean (Pacific)/Senior Lecturer Pathology & Molecular Medicine, Wellington School of Medicine & Health Sciences, University of Otago, New Zealand

    To the Editor,

    I read with keen interest the research article prepared by Takagawa T., et al. (1) and entitled: “An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis.”

    This work explored the Immunological consequences of increased LRRK2 expression in the context of therapeutic options for treating Inflammatory Bowel Disease (IBD).

    The Leucine-rich repeat kinase 2 (LRRK2) protein contains several identifiable domains and is suggested to have varying functions within different cell types. Dendritic cells (DCs) from patients with Crohn’s disease (CD) and lymphoblastoid cells lines from control participants without CD but that carried the rs11564258 high risk allele at this locus, were found to displayed elevated expression of LRRK2 mRNA and protein.

    Studies using an Lrrk2 transgenic mouse model designed to over-express LRRK2 demonstrated that within this context, these mice developed more severe colitis than control groups after exposure to dextran sodium sulfate (DSS) and was associated with lamina propria DCs displaying increased Dectin-1 induced NF-kB activation and proinflammatory cytokine secretion.

    It was also shown that autophagy was inhibited by membrane associated LRRK2 causing inactivation of Beclin-1. LRRK2 inhibitors reduced Dectin-1 induced TNF-a production by murine DCs, ameliorating DSS-induced colitis in control and Lrrk2 transgenic animals. LRRK2 inhibitors were al...

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    Competing Interests: None declared.

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