Resolution of central nervous system astrocytic and endothelial sources of CCL2 gene expression during evolving neuroinflammation

Abstract

Background: The chemokine CCL2 is a critical mediator of neuroinflammation in diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). CCL2 drives mononuclear cell infiltration into the central nervous system (CNS), alters expression and distribution of microvascular endothelial tight junction proteins, and disrupts the blood-brain and blood-spinal cord barriers. Immunohistochemistry has consistently revealed astrocytes to be a source of this chemokine during neuroinflammation, while providing less uniform evidence that CNS endothelial cells may also express CCL2. Moreover, the relative contributions of these cell types to the CNS pool of CCL2 during MS/EAE are unclear and the aim of this study was to investigate this further. Methods: CCL2 gene expression was determined by qRT-PCR in different populations of CNS cells at different times following EAE induced by immunization with MOG 35-55 peptide and adjuvants, or after injection with adjuvants alone. CNS cells types were isolated by two different protocols: bulk isolation to yield crude microvascular and parenchymal fractions (containing astrocytes, other glia, and neurons), or laser capture microdissection (LCM) to acquire more precisely microvascular endothelial cells, astrocytes or other parenchymal cells.

Glial regulation of the blood-brain barrier in health and disease

“…Loss of angiotensinogen expression in MS lesions therefore diminishes this positive effect of astrocytes on BBB function. With regard to leukocyte infiltration, three recent papers pinpointed astrocytes as being a major source of CCL2 in the CNS of EAE animals [146][147][148]. Astrocyte-derived CCL2 has the capacity to disrupt claudin-5 expression in BBB-ECs before onset of clinical symptoms and to sustain immune cell infiltration in the chronic phase of the disease.…”

Control of autoimmune CNS inflammation by astrocytes

“…Its cellular sources in the CNS have been determined by time course studies during EAE in different rodent strains (79,80) as well as elegant approaches such as Laser Capture Microdissection from different cell types in the inflamed CNS: Microvasculature endothelial cells and, to an even higher extent, astrocytes have been determined as the main resident cell sources of CCL2 in the CNS during EAE (81). …”

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment

“…MCP1 is a soluble chemoattractant protein that is produced by activated astrocytes to recruit monocytes/macrophages into CNS [20, 21]. We measured plasma MCP-1 as a comparator biomarker for this DKK1 study.…”