| Autor: |
Park, Jeongho, Lee, Jang-Won, Cooper, Scott C., Broxmeyer, Hal E., Cannon, Jason R., Kim, Chang H. |
| Zdroj: |
Journal of Leukocyte Biology; October 2017, Vol. 102 Issue: 4 p1093-1102, 10p |
| Abstrakt: |
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 LRRK2gene have been identified as risk factors for both diseases. LRRK2 G2019Sis the most prevalent mutation found in PD. To gain insights into the role of the LRRK2 G2019Sgene on the development and activation of the immune system in the brain–gut axis, we investigated the effect of LRRK2 G2019Son bone marrow myeloid progenitors and myeloid cell function in the periphery. We used bacterial artificial chromosome transgenic rats harboring the human LRRK2 G2019Sgene. LRRK2 G2019Stransgene 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 G2019Scompared 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 G2019Srats. The abnormally expanded myeloid cells because of the LRRK2 G2019Sgene 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 LRRK2activity 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 LRRK2abnormalities. |
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