Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation.
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.
Huang
D
D
Department of Neurology, and The Lerner Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.
Han
Y
Y
Rani
M R
MR
Glabinski
A
A
Trebst
C
C
Sørensen
T
T
Tani
M
M
Wang
J
J
Chien
P
P
O'Bryan
S
S
Bielecki
B
B
Zhou
Z L
ZL
Majumder
S
S
Ransohoff
R M
RM
D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D019707:Receptors, Chemokine / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D018925:Chemokines; D019707:Receptors, Chemokine