| Autor: |
Sun, Shengxiang, Hodel, Miki, Wang, Xiang, De Vicente, Javier, Haritunians, Talin, Debebe, Anketse, Hung, Chen-Ting, Ma, Changqing, Malique, Atika, Nguyen, Hoang N., Agam, Maayan, Maloney, Michael T., Goo, Marisa S., Kluss, Jillian H., Mishra, Richa, Frein, Jennifer, Foster, Amanda, Ballentine, Samuel, Pandey, Uday, Kern, Justin |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 101, p1-13, 13p |
| Abstrakt: |
LRRK2 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 LRRK2 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. Editor's summary: Specific variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased susceptibility to Crohn's disease (CD), but how LRRK2 contributes to the pathogenesis of CD is not fully understood. Using mice harboring LRRK2 risk alleles, Sun et al. found that hyperactive LRRK2 in macrophages led to impaired autophagy and Paneth cell dysfunction. Pathogenic LRRK2 kinase activity could also be triggered by deficiency of the autophagy gene ATG16L1 in combination with cigarette smoke and rescued by an LRRK2 inhibitor. Together, these findings identify a Paneth cell–extrinsic pathway by which hyperactive LRRK2 interferes with autophagy and intestinal epithelial homeostasis. —Claire Olingy [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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