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* Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands; Departments of
Neurology and
Medical Psychology, Medical Faculty, University of Essen, Essen, Germany;
Department of Medical Pharmacology, Research Institute Neurosciences, VU University Medical Center, Amsterdam, The Netherlands;
¶ Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC 27710; and
|| Department of Psychology and Behavioral Immunobiology, Swiss Federal Institute of Technology, Zürich, Switzerland
Many modulators of inflammation, including chemokines, neuropeptides, and neurotransmitters signal via G protein-coupled receptors (GPCR). GPCR kinases (GRK) can phosphorylate agonist-activated GPCR thereby promoting receptor desensitization. Here we describe that in leukocytes from patients with active relapsing-remitting multiple sclerosis (MS) or with secondary progressive MS, GRK2 levels are significantly reduced. Unexpectedly, cells from patients during remission express even lower levels of GRK2. The level of GRK2 in leukocytes of patients after stroke, a neurological disorder with paralysis but without an autoimmune component, was similar to GRK2 levels in cells from healthy individuals. In addition, we demonstrate that the course of recombinant myelin oligodendrocyte glycoprotein (1–125)-induced experimental autoimmune encephalomyelitis (EAE), an animal model for MS, is markedly different in GRK2+/– mice that express 50% of the GRK2 protein in comparison with wild-type mice. Onset of EAE was significantly advanced by 5 days in GRK2+/– mice. The earlier onset of EAE was associated with increased early infiltration of the CNS by T cells and macrophages. Although disease scores in the first phase of EAE were similar in both groups, GRK2+/– animals did not develop relapses, whereas wild-type animals did. The absence of relapses in GRK2+/– mice was associated with a marked reduction in inflammatory infiltrates in the CNS. Recombinant myelin oligodendrocyte glycoprotein-induced T cell proliferation and cytokine production were normal in GRK2+/– animals. We conclude that down-regulation of GRK2 expression may have important consequences for the onset and progression of MS.
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