Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis.
A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases. Astrocytes in the white matter of subjects with MS are deficient in beta(2) adrenergic receptors. Stimulation of beta(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). beta(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade. In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS.
De Keyser
Jacques
J
Department of Neurology, University Hospital Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Jacques.DeKeyser@uzbrussel.be
Laureys
Guy
G
Demol
Frauke
F
Wilczak
Nadine
N
Mostert
Jop
J
Clinckers
Ralph
R
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology
D018340:Receptors, Adrenergic, alpha-1