Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation

Abstract

This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte chemoattractant protein (MCP)-1 and interferon-gamma-inducible protein-10 (IP-10) are largely restricted to astrocytes or other glial cells in these diverse pathological states. The remainder of the review focuses on studies that address the molecular mechanisms which underlie transcriptional regulation of three astrocyte-derived chemokines: MCP-1, IP-10 and beta-R1/interferon-gamma-inducible T-cell chemoattractant (I-TAC). Based on these studies, we propose that the complex promoters of these genes are marvelously organized for flexible and efficient response to challenge. In the case of MCP-1, several different stimuli can elicit gene transcription, acting through a conserved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1. For IP-10 and beta-R1/I-TAC, it appears that efficient gene transcription occurs only in highly inflammatory circumstances that produce aggregates of simultaneous stimuli. These characteristics, in turn, mirror the expression patterns of the endogenous genes: MCP-1 is expressed under a variety of circumstances, while IP-10 appears primarily during immune-mediated processes that feature exposure of resident neuroglia to high levels of inflammatory cytokines.

HIV-1, chemokines and neurogenesis

“…Some chemokines are constitutively expressed at relatively high levels, and seem to be important in the normal trafficking of these cells, whereas other chemokines seem to be upregulated during inflammatory responses and to guide leukocytes to sites of inflammation (Huang et al, 2000). Of particular interest was the discovery that the cellular receptors for HIV-1, on macrophages and T-lymphocytes respectively, were the CCR5 and CXCR4 chemokine receptors.…”

“…However, this situation changes substantially during the brain's response to infection or injury. Under these circumstances, many "inflammatory" chemokines are upregulated by astrocytes as well as by microglia and neurons (Huang et al, 2000;Tran and Miller, 2003), and these chemokines serve an important function in coordinating the brain's neuroinflammatory response. Indeed, the role of brain-derived chemokines in controlling the trafficking of leukocytes into the brain during neuroinflammation has been clearly demonstrated (Babcock et al, 2003).…”

“…MCP-1, and other members of the MCP family, exert their effects primarily on CCR2 receptors. Other chemokines, which have been frequently observed to be upregulated in neuroinflammatory disease include IP-10 (CXCR3), RANTES (CCR5), and MIP-1α (CCR1) (Huang et al, 2000). Nearly all types of brain infection, trauma, seizure activity or neurodegenerative disease are accompanied by neuroinflammatory phenomena, which results in the synthesis of chemokines and a variety of "proinflammatory" cytokines.…”

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase

“…Although inflammation is an important host defense mechanism, severe inflammation aggravates tissue injury (Lee et al, 1993;Huang et al, 2000;Dong and Benveniste, 2001;Mrak and Griffin, 2001). Thus, negative regulation of cytokine signaling is important for limiting the intensity and duration of cytokine action and for maintaining homeostasis.…”

“…In response to brain damage, astrocytes produce inflammatory mediators, such as cytokines, chemokines, and cell adhesion molecules (Lee et al, 1993;Ridet et al, 1997). These inflammatory mediators can aggravate brain damage, resulting in the enhancement of the onset and progression of neurodegenerative dis-eases (Huang et al, 2000;Dong and Benveniste, 2001;Mrak and Griffin, 2001). Therefore, it is pathophysiologically important to control the extent and duration of inflammation.…”