Parkinson disease-associated LRRK2 G2019s transgene disrupts marrow myelopoiesis and peripheral Th17 response

Jeongho Park, Jang Won Lee, Scott C. Cooper, Hal Broxmeyer, Jason R. Cannon, Chang H. Kim

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease, whereas Crohn’s disease is an inflammatory bowel disease. Interestingly, polymorphisms in the LRRK2 gene have been identified as risk factors for both diseases. LRRK2 G2019S is the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019S gene on the development and activation of the immune system in the brain-gut axis, we investigated the effect of LRRK2 G2019S on bonemarrow myeloid progenitors and myeloid cell function in the periphery. We used bacterial artificial chromosome transgenic rats harboring the human LRRK2 G2019S gene. LRRK2 G2019S transgene decreased the numbers of monocytic and granulocytic progenitors in the bone marrow. However, the numbers of peripheral, immature myeloid cells with suppressive activity were increased in the gut and blood circulation of LRRK2 G2019S compared with control rats in various acute and chronic inflammatory responses. In inflammatory conditions, Th17 cell activity was suppressed, but tissueassociated phylum Bacteroidetes was abnormally increased in the intestine of LRRK2 G2019S rats. The abnormally expanded myeloid cells because of the LRRK2 G2019S gene were highly suppressive on Th17 cell differentiation. Moreover, we found that inhibition of LRRK2 kinase affects myeloid progenitors and myeloid cell differentiation. Taken together, the results indicate that abnormal LRRK2 activity can alter bone marrow myelopoiesis, peripheral myeloid cell differentiation, and intestinal immune homeostasis. These findings may have ramifications in immune and inflammatory responses in patients with LRRK2 abnormalities.

Original languageEnglish (US)
Pages (from-to)1093-1102
Number of pages10
JournalJournal of Leukocyte Biology
Volume102
Issue number4
DOIs
StatePublished - Oct 1 2017

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Myelopoiesis
Myeloid Cells
Transgenes
Parkinson Disease
Bone Marrow
Th17 Cells
Cell Differentiation
Genes
Bacteroidetes
Transgenic Rats
Bacterial Artificial Chromosomes
Blood Circulation
Inflammatory Bowel Diseases
Crohn Disease
Neurodegenerative Diseases
Intestines
Immune System
Homeostasis
Phosphotransferases
Mutation

Keywords

  • Crohn
  • Inflammation
  • Intestine
  • Myeloid cells
  • T cells

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

Parkinson disease-associated LRRK2 G2019s transgene disrupts marrow myelopoiesis and peripheral Th17 response. / Park, Jeongho; Lee, Jang Won; Cooper, Scott C.; Broxmeyer, Hal; Cannon, Jason R.; Kim, Chang H.

In: Journal of Leukocyte Biology, Vol. 102, No. 4, 01.10.2017, p. 1093-1102.

Research output: Contribution to journalArticle

Park, Jeongho ; Lee, Jang Won ; Cooper, Scott C. ; Broxmeyer, Hal ; Cannon, Jason R. ; Kim, Chang H. / Parkinson disease-associated LRRK2 G2019s transgene disrupts marrow myelopoiesis and peripheral Th17 response. In: Journal of Leukocyte Biology. 2017 ; Vol. 102, No. 4. pp. 1093-1102.
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