Many neurologic diseases such as Alzheimer's disease, viral encephalitis, and brain trauma are characterized by infiltration of peripheral immune cells that mediate inflammation, injury, and/or repair. Monocytes are an important component of these infiltrating cells, functioning to secrete effector cytokines and chemokines to recruit and activate other cells, to kill pathogens and infected cells, and to present antigen to te adaptive immune system. The process of immune cell recruitment is controlled by chemokines binding to Gay-protein coupled chemokine receptors (CRs). Regulator of G-protein signaling (RGS) 10, a GTPase accelerating protein (GAP) that acts on Gai, has been shown to regulate activation, intracellular signaling, and chemokine and CR expression of microglia, a myeloid-derived central nervous system (CNS)-resident cell. Given a shared myeloid origin, RGS10 likely plays a role in mediating the Gai-coupled chemokine receptor signaling in monocytes, cells which migrate to sites of inflammation to modulate inflammation and engage adaptive immune mechanisms. Although expression of RGS10 is enriched in various subsets of immune cells, RGS10's physiologic substrates have not been identified. In this study, we will first identiy CRs functionally coupled to RGS10 by testing in vitro monocyte responses (rolling, integrin activation, static adhesion, tight binding, and chemotaxis) to chemokines that are known to be important for recruitment of monocytes to the CNS and that we have shown to have dysregulated gene expression in RGS10-null microglia. Secondly, we will assess whether the dynamics of monocyte chemotaxis are altered in an RGS10-null mouse through in vivo measurement of monocyte recruitment in models of acute and chronic CNS inflammation. By elucidating mechanisms through which RGS10 regulates monocyte chemotaxis, we will reveal opportunities for treatment of neurologic diseases where peripheral immune cells play a dynamic and important role.

Public Health Relevance

The goal of this project is to elucidate the role of the regulator of G-protein signaling 10 (RGS10) protein in regulating monocyte chemotaxis to inflammation in the central nervous system (CNS). Since monocyte infiltration into the CNS is involved in many neurologic diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis, understanding mechanisms that control this process can lead to opportunities to develop novel disease-modifying immunomodulatory therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS081830-02
Application #
8703544
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Sieber, Beth-Anne
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lee, Jae-Kyung; Kannarkat, George T; Chung, Jaegwon et al. (2016) RGS10 deficiency ameliorates the severity of disease in experimental autoimmune encephalomyelitis. J Neuroinflammation 13:24
Moehle, Mark S; Daher, João Paulo Lima; Hull, Travis D et al. (2015) The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. Hum Mol Genet 24:4250-67
Kannarkat, G T; Cook, D A; Lee, J-K et al. (2015) Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study. NPJ Parkinsons Dis 1:
Kannarkat, George T; Lee, Jae-Kyung; Ramsey, Chenere P et al. (2015) Age-related changes in regulator of G-protein signaling (RGS)-10 expression in peripheral and central immune cells may influence the risk for age-related degeneration. Neurobiol Aging 36:1982-93
Kannarkat, George T; Boss, Jeremy M; Tansey, Malú G (2013) The role of innate and adaptive immunity in Parkinson's disease. J Parkinsons Dis 3:493-514
Lee, Jae-Kyung; Chung, Jaegwon; Kannarkat, George T et al. (2013) Critical role of regulator G-protein signaling 10 (RGS10) in modulating macrophage M1/M2 activation. PLoS One 8:e81785