FcεRII/CD23 Is Expressed in Parkinson’s Disease and Induces,In Vitro,Production of Nitric Oxide and Tumor Necrosis Factor-α in Glial Cells

Abstract

Oxidative stress is thought to be involved in the mechanism of nerve cell death in Parkinson's disease (PD). Among several toxic oxidative species, nitric oxide (NO) has been proposed as a key element on the basis of the increased density of glial cells expressing inducible nitric oxide synthase (iNOS) in the substantia nigra (SN) of patients with PD. However, the mechanism of iNOS induction in the CNS is poorly understood, especially under pathological conditions. Because cytokines and FcepsilonRII/CD23 antigen have been implicated in the induction of iNOS in the immune system, we investigated their role in glial cells in vitro and in the SN of patients with PD and matched control subjects. We show that, in vitro, interferon-gamma (IFN-gamma) together with interleukin-1beta (Il-1beta) and tumor necrosis factor-alpha (TNF-alpha) can induce the expression of CD23 in glial cells. Ligation of CD23 with specific antibodies resulted in the induction of iNOS and the subsequent release of NO. The activation of CD23 also led to an upregulation of TNF-alpha production, which was dependent on NO release. In the SN of PD patients, a significant increase in the density of glial cells expressing TNF-alpha, Il-1beta, and IFN-gamma was observed. Furthermore, although CD23 was not detectable in the SN of control subjects, it was found in both astroglial and microglial cells in parkinsonian patients. Altogether, these data demonstrate the existence of a cytokine/CD23-dependent activation pathway of iNOS and of proinflammatory mediators in glial cells and their involvement in the pathophysiology of PD.

Synergistic Dopaminergic Neurotoxicity of the Pesticide Rotenone and Inflammogen Lipopolysaccharide: Relevance to the Etiology of Parkinson's Disease

“…SOD-catalase (100 and 150 U/ml, respectively) were added at the same time with rotenone and LPS. Seven days later, neurotoxicity was determined by PD have derived from postmortem analyses of PD brains in which microglial activation, elevated levels of proinflammatory mediators such as TNF␣, IL-1␤, and NO, and evidence of ROS production have been detected in the substantia nigra (McGeer et al, 1988;Cassarino et al, 1997;Hunot et al, 1999;Nagatsu et al, 2000). However, it is not clear whether these inflammatory "footprints" observed in the late stages of the pathogenesis of PD may merely be a reflection of reactive gliosis after the occurrence of the initial neuronal injuries.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In addition to oxidative stress also other mechanisms have been proposed to be involved in selective DA neuron degeneration in PD, including excitotoxicity, intracellular calcium and metal ion rise, neurofibrillary tangle formation and disruption of the cytoskeletal transport [112]. More recently, neuroinflammation and microglial activation have been implicated in the neurodegenerative process in PD, as initially suggested by McGeer et al [155] and then by several authors ( [77,89,95,97,104,102,107,148,168]). In fact, studies accumulated over the last two decades have clearly indicated the presence of an abnormal glial response in postmortem nervous system of PD patients.…”

Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease

“…No staining was observed under these conditions. Fluorescent double-staining experiments were performed on mesencephalic sections mounted on gelatin-double-coated slides, as described previously (23), to analyze simultaneously caspase-3 and TH.…”