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

Tetsuya Takagawa, Atsushi Kitani, Ivan Fuss, Beth Levine, Steven R. Brant, Inga Peter, Masaki Tajima, Shiro Nakamura, Warren Strober

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19 Scopus citations

Abstract

The LRRK2/MUC19 gene region constitutes a high-risk genetic locus for the occurrence of both inflammatory bowel diseases (IBDs) and Parkinson’s disease. We show that dendritic cells (DCs) from patients with Crohn’s disease (CD) and lymphoblastoid cell lines derived from patients without CD but bearing a high-risk allele (rs11564258) at this locus as heterozygotes exhibited increased LRRK2 expression in vitro. To investigate the immunological consequences of this increased LRRK2 expression, we conducted studies in transgenic mice overexpressing Lrrk2 and showed that these mice exhibited more severe colitis induced by dextran sodium sulfate (DSS) than did littermate control animals. This increase in colitis severity was associated with lamina propria DCs that showed increased Dectin-1–induced NF-B activation and proinflammatory cytokine secretion. Colitis severity was driven by LRRK2 activation of NF-B pathway components including the TAK1 complex and TRAF6. Next, we found that membrane-associated LRRK2 (in association with TAB2) caused inactivation of Beclin-1 and inhibition of autophagy. HCT116 colon epithelial cells lacking Beclin-1 exhibited increased LRRK2 expression compared to wild-type cells, suggesting that inhibition of autophagy potentially could augment LRRK2 proinflammatory signaling. We then showed that LRRK2 inhibitors decreased Dectin-1–induced TNF- production by mouse DCs and ameliorated DSS-induced colitis, both in control and Lrrk2 transgenic animals. Finally, we demonstrated that LRRK2 inhibitors blocked TNF- production by cultured DCs from patients with CD. Our findings suggest that normalization of LRRK2 activation could be a therapeutic approach for treating IBD, regardless of whether a LRRK2 risk allele is involved.

Original languageEnglish (US)
Article numbereaan8162
JournalScience Translational Medicine
Volume10
Issue number444
DOIs
StatePublished - Jun 6 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Takagawa, T., Kitani, A., Fuss, I., Levine, B., Brant, S. R., Peter, I., Tajima, M., Nakamura, S., & Strober, W. (2018). An increase in LRRK2 suppresses autophagy and enhances dectin-1–induced immunity in a mouse model of colitis. Science Translational Medicine, 10(444), [eaan8162]. https://doi.org/10.1126/scitranslmed.aan8162