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Review
, 37 (6), 625-38

Control of Autoimmune CNS Inflammation by Astrocytes

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Review

Control of Autoimmune CNS Inflammation by Astrocytes

Veit Rothhammer et al. Semin Immunopathol.

Abstract

Multiple sclerosis is a neurologic disease caused by immune cell infiltration into the central nervous system, resulting in gray and white matter inflammation, progressive demyelination, and neuronal loss. Astrocytes, the most abundant cell population in the central nervous system (CNS), have been considered inert scaffold or housekeeping cells for many years. However, recently, it has become clear that this cell population actively modulates the immune response in the CNS at multiple levels. While being exposed to a plethora of cytokines during ongoing autoimmune inflammation, astrocytes modulate local CNS inflammation by secreting cytokines and chemokines, among other factors. This review article gives an overview of the most recent understanding about cytokine networks operational in astrocytes during autoimmune neuroinflammation and highlights potential targets for immunomodulatory therapies for multiple sclerosis.

Keywords: Astrocyte; Blood-brain barrier; Chemokine; Cytokine; Multiple sclerosis.

Figures

Figure 1
Figure 1. Cellular sources of cytokines that impact astrocyte biology during autoimmune CNS inflammation
Signature cytokines of CNS infiltrating T cell subsets including Th1, Th17, Treg and Tr1 cells influence astrocyte biology and direct their behavior. Moreover, monocytes, macrophages as well as resident microglia secret IL-1β and IL-6, among others, and influence the local cytokine environment, blood brain barrier integrity and astrocyte and neuronal function.
Figure 2
Figure 2. Cytokines and chemokines produced by astrocytes regulate CNS inflammation at multiple levels
Astrocytes create a chemoattractant gradients that guide immune cell infiltration into the CNS, shape the local cytokine milieu to influence recruited and resident cells in the CSN such monocytes and oligodendrocytes and ultimately determine the outcome after local inflammation.
Figure 3
Figure 3. Biology of CCL2 production by astrocytes
Pro-inflammatory stimuli like LPS, IL-1β, TNF-α, IFN-γ or glycolipids (1), activate NF-κB and stat1 signaling in astrocytes. These transcription factors bind to the CCL2 promoter and its enhancer (2). Favored by their intimate location at the blood brain barrier, astrocytes secrete CCL2 into the circulation (3) creating a chemotactic gradient for cells expressing CCR2 such as T cells, mast cells, monocytes or macrophages (4), which are guided to the site of inflammation (5). Also, autocrine effects of CCL2 upon binding of its receptors CCR2 and L-CCR, both expressed on astrocytes, lead to astrocytic migration towards a CCL2 gradient as well as reduced apoptosis (6).

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