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

Lrrking in the shadows of colitis

In new work, Takagawa et al. show that dendritic cells (DCs) from Crohn’s disease (CD) patients and lymphoblastoid cells from control patients bearing a single-nucleotide polymorphism (SNP) in the LRRK2/MUC19 gene region exhibited increased LRRK2 mRNA and protein expression. Lrrk2 transgenic mice overexpressing LRRK2 compared to littermate control mice showed more severe colitis induced by the chemical DSS and increased Dectin-1–induced proinflammatory cytokine secretion driven by LRRK2 activation of the NF-κB signaling pathway. Membrane-associated LRRK2 inactivated Beclin-1 and consequently inhibited autophagy. Finally, the authors demonstrate that LRRK2 inhibitors decreased Dectin-1–induced TNF-α production by DCs and ameliorated DSS-induced colitis in both control and Lrrk2 transgenic mice, suggesting that LRRK2 inhibitors should be investigated further as a potential treatment for CD.

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