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Sci Transl Med. 2018 Jun 6;10(444). pii: eaan8162. doi: 10.1126/scitranslmed.aan8162.

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

Author information

1
Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
2
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3
Departments of Internal Medicine and Microbiology, Center for Autophagy Research, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21287, USA.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. wstrober@niaid.nih.gov.

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-κB activation and proinflammatory cytokine secretion. Colitis severity was driven by LRRK2 activation of NF-κB 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-α production by mouse DCs and ameliorated DSS-induced colitis, both in control and Lrrk2 transgenic animals. Finally, we demonstrated that LRRK2 inhibitors blocked TNF-α 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.

PMID:
29875204
PMCID:
PMC6636639
DOI:
10.1126/scitranslmed.aan8162
[Indexed for MEDLINE]
Free PMC Article

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