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.
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.
