CNS inflammation in nervous and mental disease

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

The chemokine CCL2 is considered a significant factor in multiple sclerosis (MS), and plays a primary pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Though CCL2 nonredundantly functions in EAE to promote accumulation of destructive leukocytes in the central nervous system (CNS), as well as possibly other manifestations of neuroinflammation, neither the pathogenic source(s) of this chemokine, nor its site(s) and mechanism(s) of action, are known. And while astrocytes and endothelial cells are recognized as major sources of CCL2 during EAE, no descriptions have yet reconciled whether and how production of CCL2 by either of these cells leads to leukocyte extravasation and invasion of the CNS parenchyma. This deficiency leaves a significant void in understanding MS/EAE pathogenesis, and seriously impacts novel treatments for MS, as the potential of anti-CCL2 therapy is critically dependent on effectively disrupting the specific chemokine pool(s) responsible for disease activity. Accordingly, experiments are designed to begin testing the following broad hypothesis: Cell-specific release of CCL2 regulates discrete aspects of neuroinflammation during EAE. Aim 1 will focus on performing the first high-resolution analysis of CCL2 protein distribution in the CNS throughout the course of EAE, which will provide insight into those pathways of communication between centrally derived CCL2 and blood-borne leukocytes critical for guiding extravastion. Aim 2 will then employ two novel, cell-conditional CCL2 knockout lines - suffering targeted CCL2 elimination in astrocytes or endothelial cells - to determine the respective contributions of each of these cell types to clinical disease. These experiments will provide a foundation for future studies to further resolve the mechanisms by which CCL2 promotes leukocyte extravastion into the CNS, and highlight therapeutic avenues to most efficiently disrupt CCL2 action during CNS inflammatory disease.