ABSTRACT
Title
RANTES-glutamate interaction in Central Nervous System: a glial to neuron cross-talk relevant to central neuroinflammation
Authors
S. Di Prisco1, M. Summa1, V. Chellakudam1 and A. Pittaluga1,2.
1Department of Experimental Medicine, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy, and 2 Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
1Department of Experimental Medicine, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy, and 2 Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
Abstract
For many decades there has been a general consensus that the immune and the central nervous systems were independent. This theory has been challenged by the observations that i) immune cells infiltrate the central nervous system (CNS) in neurological diseases and ii) a number of endogenous molecules (i.e the chemokines for the immuno system and classic neurotransmitters for the nervous system) are shared in common between the two systems. Our work was aimed at investigating the functional cross-talk between endogenous factors released by immune cells (i.e. the chemokine Regulated upon Activation Normal T cell Expressed and Secreted, RANTES) and classic neurotransmitters (i.e. glutamate, GLU). Previous results showed that, in human cortex, RANTES could exert a dual role on GLU release.
Considering that GLU itself can control the production and the release of RANTES from activated glial cells (Besong et al. 2002), it seems reasonable to propose that GLU and RANTES are principal actors in the interaction between immune and neuronal systems. The study was then extended to investigate the effect of RANTES on the release of glutamate from nerve endings (synaptosomes) and glial particles (gliosomes) isolated from the cortex and the spinal cord of adult mice.
Our results demonstrate that RANTES facilitates the spontaneous release of [3H]D-aspartate ([3H]D-ASP) from cortical synaptosomes but failes to affect glutamate outflow from spinal cord synaptosomes as well as from cortical and spinal cord gliosomes. The releasing effect is prevented by selective antagonists at CCR1 and CCR5 receptors (the compounds BX513 and DAPTA, respectively). RANTES inhibites the K+-evoked release of [3H]D-ASP from cortical synaptosomes but potentiates the K+-induced [3H]D-ASP exocytosis from spinal cord terminals. Inhibition of glutamate exocytosis in the cortex is prevented by antagonists acting at CCR1, CCR3 and CCR5 receptors, while facilitation of glutamate exocytosis in spinal cord is insensitive to CCR3 antagonist (the compound SB328437) but prevented by CCR1 and CCR5 antagonists. It is concluded that glutamate transmission can be modulated in a area-specific manner and in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.
This work was supported by grants from “Italian Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica” and from Bandi FISM Project n° 2008/R/21
Considering that GLU itself can control the production and the release of RANTES from activated glial cells (Besong et al. 2002), it seems reasonable to propose that GLU and RANTES are principal actors in the interaction between immune and neuronal systems. The study was then extended to investigate the effect of RANTES on the release of glutamate from nerve endings (synaptosomes) and glial particles (gliosomes) isolated from the cortex and the spinal cord of adult mice.
Our results demonstrate that RANTES facilitates the spontaneous release of [3H]D-aspartate ([3H]D-ASP) from cortical synaptosomes but failes to affect glutamate outflow from spinal cord synaptosomes as well as from cortical and spinal cord gliosomes. The releasing effect is prevented by selective antagonists at CCR1 and CCR5 receptors (the compounds BX513 and DAPTA, respectively). RANTES inhibites the K+-evoked release of [3H]D-ASP from cortical synaptosomes but potentiates the K+-induced [3H]D-ASP exocytosis from spinal cord terminals. Inhibition of glutamate exocytosis in the cortex is prevented by antagonists acting at CCR1, CCR3 and CCR5 receptors, while facilitation of glutamate exocytosis in spinal cord is insensitive to CCR3 antagonist (the compound SB328437) but prevented by CCR1 and CCR5 antagonists. It is concluded that glutamate transmission can be modulated in a area-specific manner and in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.
This work was supported by grants from “Italian Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica” and from Bandi FISM Project n° 2008/R/21