Science immunology · 2024
Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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, Yang Shaohong, Mengesha Emebet, Balasubramanian Iyshwarya, Arguello Annie, Estrada Anthony A, Gao Nan, Peter Inga, McGovern Dermot P B, Henry Anastasia G, Stappenbeck Thaddeus S, Liu Ta-Chiang
Аннотация
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.