Parkinson disease–associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response

• Published in: Journal of leukocyte biology Vol. 102; no. 4; pp. 1093 - 1102
• Main Authors: Park, Jeongho, Lee, Jang‐Won, Cooper, Scott C., Broxmeyer, Hal E., Cannon, Jason R., Kim, Chang H.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD, USA Society for Leukocyte Biology 01-10-2017; Oxford University Press
• Subjects: Abnormalities; Amino Acid Substitution; Animals; Artificial chromosomes; Bacteria; Blood circulation; Bone marrow; Brain; Cell Development, Differentiation, & Trafficking; Cell differentiation; Crohn; Differentiation (biology); Digestive system; Disease; Gastrointestinal tract; Health risks; Helper cells; Homeostasis; Immune system; inflammation; Inflammatory bowel diseases; Intestine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - immunology; LRRK2 protein; Lymphocytes T; Monocytes; Movement disorders; Mutation, Missense; Myeloid cells; Myelopoiesis; Myelopoiesis - genetics; Myelopoiesis - immunology; Neurodegenerative diseases; Osteoprogenitor cells; Parkinson Disease - genetics; Parkinson Disease - immunology; Parkinson's disease; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Risk analysis; Risk factors; Rodents; T cells; Th17 Cells - immunology; Th17 Cells - pathology; Transgenes; Transgenes - immunology; Crohn; intestine; myeloid cells; T cells; inflammation
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1A0417-147RR

The PD‐associated LRRK2 G2019S gene abnormally alters marrow myelopoiesis and peripheral myeloid cell differentiation, leading to decreased Th17 cell activity.
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 bone marrow 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 tissue‐associated 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.