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Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction

Shengxiang Sun1, Miki Hodel1, Xiang Wang2

  • 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Science Immunology
|November 8, 2024
PubMed

Insights

Genetic variants in LRRK2 (Leucine-rich repeat kinase 2) influence Parkinson's and Crohn's disease risk. LRRK2 kinase inhibitors may treat Crohn's disease by restoring Paneth cell function and autophagy.

Area of Science:

  • Gastroenterology
  • Immunology
  • Genetics

Background:

  • LRRK2 (Leucine-rich repeat kinase 2) polymorphisms are linked to increased risk of Parkinson's disease and Crohn's disease (CD).
  • Hyperactive LRRK2 kinase activity suppresses autophagy, a critical process for maintaining Paneth cell homeostasis.
  • Paneth cell dysfunction is implicated in the gut inflammation characteristic of CD.

Purpose of the Study:

  • To investigate the role of LRRK2 in Paneth cell dysfunction in CD.
  • To explore LRRK2 kinase inhibition as a potential therapeutic strategy for CD.

Main Methods:

  • Analysis of LRRK2 polymorphisms in CD patients and mouse models.
  • Assessment of Paneth cell function and autophagy.
  • Investigation of LRRK2 expression in intestinal cells.
  • Evaluation of LRRK2 kinase inhibition effects on Paneth cell function and autophagy.

Main Results:

  • CD patients and mice with hyperactive LRRK2 polymorphisms exhibited Paneth cell dysfunction.
  • LRRK2 kinase was found to be expressed in lamina propria immune cells, not Paneth cells.
  • LRRK2-mediated pro-inflammatory cytokine release impaired Paneth cell function.
  • LRRK2 kinase inhibition restored autophagy and rescued Paneth cell function.

Conclusions:

  • LRRK2 kinase hyperactivity contributes to Paneth cell dysfunction in CD.
  • LRRK2 kinase inhibitors may represent a novel therapeutic approach for CD by restoring autophagy and Paneth cell homeostasis.

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