# Macrophage LRRK2 activity regulates gut epithelial homeostasis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $429,180

## Abstract

ABSTRACT
Crohn’s disease (CD) pathogenesis includes gene-environment interactions. GWAS have identified >100 CD
susceptibility genes. Among the CD susceptibility genes, LRRK2 is of particular interest. It is associated with
autophagy regulation and is also a Parkinson disease (PD) susceptibility gene. The same LRRK2 single
nucleotide polymorphisms (SNPs) that increase susceptibility to PD and CD (G2019S, N2081D) result in
LRRK2 kinase hyperactivity. This is of clinical relevance, as LRRK2-targeted therapies are being developed for
PD. Understanding how LRRK2 hyperactivity contribute to CD pathogenesis will broaden therapeutic options
for CD. We find that in the gut, LRRK2 is expressed predominantly in phagocytes (e.g., macrophages) instead
of epithelial cells. We also find that in hosts without LRRK2 risk SNPs, LRRK2 kinase can be activated by
gene-environment interactions involving autophagy gene SNP (ATG16L1 T300A) and cigarette smoking. We
previously showed that such T300A-smoking interaction results in functional defects of small intestinal Paneth
cells, an epithelial cell type with innate immune function. We find that CD patients harboring LRRK2 risk SNPs,
Lrrk2 G2019S mice, and T300A-smoked mice are all prone to develop Paneth cell defects, and this is driven
by macrophage LRRK2 hyperactivity. Our data suggests a key role of macrophage LRRK2 kinase activity in
gut inflammation. The critical questions that need to be addressed before translating these findings to clinic
include how LRRK2 kinase is activated in hosts without LRRK2 SNPs, and whether additional CD susceptibility
genes contribute to macrophage LRRK2 kinase hyperactivity. Our long-term goal is to provide mechanistic
insight and therapeutic strategies for CD patients. The central hypothesis is that macrophage LRRK2 kinase
activity is critical in epithelial homeostasis. Our rationale is that identification of the mechanism(s) to restore
proper macrophage LRRK2 levels will offer new therapeutic opportunities for CD. Our specific aims will test the
following hypotheses: (1) autophagy deficiency sensitizes macrophages to increased reactive oxygen species
production upon cigarette smoking, which then activates LRRK2 kinase; (2) additional CD susceptibility genes
also contribute to LRRK2 kinase activation. This contribution is significant since it will establish LRRK2 kinase
as a CD therapeutic target. The proposed research is innovative because we investigate how LRRK2 kinase
activity is central to maintaining gut homeostasis, a heretofore-unexamined process. We also use state-of-the-
art air-liquid interface culture and spatial transcriptomics to identify molecular and cellular targets that affect
macrophage LRRK2 kinase activities. Identifying the mechanisms of how LRRK2 regulates a key disease-
relevant phenotype will provide insight into other inflammatory disorders.

## Key facts

- **NIH application ID:** 10983397
- **Project number:** 1R01DK138465-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ta-Chiang Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,180
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10983397

## Citation

> US National Institutes of Health, RePORTER application 10983397, Macrophage LRRK2 activity regulates gut epithelial homeostasis (1R01DK138465-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10983397. Licensed CC0.

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