Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction
<i>LRRK2</i> polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive <i>LRRK2</i> polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.
Authors
- Maayan Agam (ORCID: https://orcid.org/0000-0002-7336-3457)
- Shaohong Yang
- Talin Haritunians (ORCID: https://orcid.org/0000-0002-9005-7750)
- Samuel Ballentine (ORCID: https://orcid.org/0000-0002-6339-548X)
- Annie Arguello (ORCID: https://orcid.org/0000-0002-0313-0041)
- Anketse Debebe
- Dermot McGovern (ORCID: https://orcid.org/0000-0001-5621-759X)
- Richa Mishra (ORCID: https://orcid.org/0000-0001-8786-8432)
- Nan Gao (ORCID: https://orcid.org/0000-0003-4264-7438)
- Iyshwarya Balasubramanian
- Emebet Mengesha (ORCID: https://orcid.org/0000-0001-7830-1557)
- Shengxiang Sun (ORCID: https://orcid.org/0000-0001-5889-3292)
- Ta‐Chiang Liu (ORCID: https://orcid.org/0000-0002-2800-9360)
- Inga Peter
- Thaddeus S. Stappenbeck (ORCID: https://orcid.org/0000-0002-6023-3901)
- Jillian H. Kluss (ORCID: https://orcid.org/0000-0002-6262-6661)
- Anthony A. Estrada (ORCID: https://orcid.org/0000-0001-7615-5912)
- Marisa S. Goo (ORCID: https://orcid.org/0000-0002-1755-5649)
- Anastasia G. Henry (ORCID: https://orcid.org/0000-0002-8124-5477)
- Hoang N. Nguyen (ORCID: https://orcid.org/0000-0001-6608-7581)
- Chen‐Ting Hung (ORCID: https://orcid.org/0000-0003-0143-8445)
- Atika Malique (ORCID: https://orcid.org/0009-0007-1567-4154)
- Michael T. Maloney (ORCID: https://orcid.org/0000-0002-1805-1477)
- Justin Kern (ORCID: https://orcid.org/0009-0008-8219-7623)
- Uday Pandey (ORCID: https://orcid.org/0000-0002-8674-7257)
- Jennifer Frein
- Miki Hodel
- Xiang Wang (ORCID: https://orcid.org/0000-0001-5134-1292)
- Changqing Ma (ORCID: https://orcid.org/0000-0002-6117-9505)
- Javier de Vicente (ORCID: https://orcid.org/0000-0003-2498-0843)
- Amanda Foster
Institutions
- Rutgers, The State University of New Jersey (US)
- Cedars-Sinai Medical Center (US)
- Washington University in St. Louis (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Denali Therapeutics (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1126/sciimmunol.adi7907
- Citations
- 11
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.25
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Leona M. and Harry B. Helmsley Charitable Trust