Role of astrocytes and chemokine systems in acute TNFα induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NF-κB and Akt

Abstract

Chemotactic factors known as chemokines play an important role in the pathogenesis of Multiple Sclerosis (MS). Transgenic expression of TNFα in the central nervous system (CNS) leads to the development of a demyelinating phenotype (TNFα-induced demyelination; TID) that is highly reminiscent of MS. Little is known about the role of chemokines in TID but insights derived from studying this model might extend our current understanding of MS pathogenesis and complement data derived from the classic autoimmune encephalomyelitis (EAE) model system. Here we show that in TID, chemokines and their receptors were significantly increased during the acute phases of disease. Notably, the CCL2 (MCP-1)-CCR2 axis and the closely related ligand-receptor pair CCR1-CCL3 (MIP-1α) were among the most up-regulated during disease. On the other hand, receptors like CCR3 and CCR4 were not elevated. This significant increase in the levels of chemokines/receptors correlated with robust immune infiltration of the CNS by inflammatory cells, i.e., macrophages, and immune cells particularly T and B cells. Immunostaining and confocal microscopy, along with in vitro studies revealed that astrocytes were a major source of locally produced chemokines and expressed functional chemokine receptors such as CCR2. Using an in vitro system we demonstrate Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. that expression of CCR2 was functional in astrocytes and that signaling via this receptor lead to activation of NF-kB and Akt and was associated with increased astrocyte survival. Collectively, our data suggests that transgenic murine models of MS are useful to dissect mechanisms of disease and that in these models, up-regulation of chemokines and their receptors may be key determinants in TID. NIH Public Access

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…The target of CCL2, involved in mediating the neuroprotective activity of the chemokine, has not been addressed in the present study: previous reports showed that the main receptor for CCL2 is CCR2, but this chemokine can also bind to other receptors like CCR1, CCR4, and L-CCR, albeit with lower affinity Savarin-Vuaillat et al, 2007;White et al, 2007;Quinones et al, 2008). In addition, CCR2 expression in brain parenchyma is controversial.…”

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“…RNase protection assay (RPA) was performed as described previously (23, 29). Total RNA was isolated from homogenized ear explants and used to perform the RPA using RiboQuant Multiprobe RNase Protection Assay Kit (BD Biosciences).…”