A monoclonal antibody against peripheral benzodiazepine receptor activates the human neutrophil NADPH-oxidase

Zavala, Flora; Masson, Annie; Brys, Lea; Baetseĺier, Patrick De; Descamps‐Latscha, Béatrice

doi:10.1016/0006-291x(91)90468-m

Cited by 24 publications

(8 citation statements)

References 19 publications

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“…Mammalian TSPO is ubiquitously expressed in the body and primarily localized to the mitochondria, where it is involved in many cellular functions. However, the TSPO protein has also been shown to be present in the plasma membrane of red blood cell, a cell that has lost both the nucleus and mitochondria (38), as well as in the plasma membrane of neutrophils detected by immunoprecipitation and immunocytochemistry, where it was shown to stimulate NADPH-oxidase activation of these cells (39). The plasma membrane and mitochondrial forms of TSPO must have some implications for its putative function, including steroidogenesis, mitochondrial respiration, heme metabolism, calcium channel modulation, cell growth, and immunomodulation (40).…”

Section: Discussionmentioning

confidence: 99%

Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis

Fan

Rone

Papadopoulos

2009

Journal of Biological Chemistry

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Translocator protein (TSPO) is an 18-kDa cholesterol-and drug-binding protein conserved from bacteria to humans. While surveying for Tspo-like genes, we identified its paralogous gene, Tspo2, encoding an evolutionarily conserved family of proteins that arose by gene duplications before the divergence of avians and mammals. Comparative analysis of Tspo1 and Tspo2 functions suggested that Tspo2 has become subfunctionalized, typical of duplicated genes, characterized by the loss of diagnostic drug ligandbinding but retention of cholesterol-binding properties, hematopoietic tissue-and erythroid cell-specific distribution, and subcellular endoplasmic reticulum and nuclear membrane localization. Expression of Tspo2 in erythroblasts is strongly correlated with the down-regulation of the enzymes involved in cholesterol biosynthesis. Overexpression of TSPO2 in erythroid cells resulted in the redistribution of intracellular free cholesterol, an essential step in nucleus expulsion during erythrocyte maturation. Taken together, these data identify the TSPO2 family of proteins as mediators of cholesterol redistribution-dependent erythroblast maturation during mammalian erythropoiesis.Translocator protein (TSPO) 2 is an 18-kDa protein that was previously known as PBR (peripheral type benzodiazepine receptor) and represents a gene family evolutionarily conserved from bacteria to humans (1). In bacteria, TSPO is the tryptophan-rich sensory protein, an integral membrane protein that acts as a negative regulator of the expression of specific photosynthesis genes in response to oxygen and light (2). It is involved in the efflux of porphyrin intermediates from the cell, and several conserved aromatic residues within TSPO are thought to be involved in binding porphyrin intermediates (2). TSPO of bacterial origin has been shown to have the same ligand binding properties as mammalian TSPO proteins (3). In addition to the binding of porphyrin and heme, mammalian TSPO can replace the activity of its bacterial homologs (2, 4, 5). Rat TSPO was shown to retain its structure within the bacterial outer membrane, to functionally substitute for the bacterial homolog, and to act in a manner similar to TSPO in the outer mitochondrial membrane (6). Therefore, it is conceivable that some conserved functions of the Tspo genes within a cell are maintained from bacteria to plants and to mammals.In mammals, the biological significance of TSPO has been studied for decades, and TSPO has been shown to be involved in a variety of cellular functions, including cholesterol transport and steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and proliferation (7-10). Moreover, its expression correlates with certain pathological conditions such as cancer and endocrine and neurological diseases (8). Although some conserved cellular functions of Tspo are shared from bacteria to mammals, such as cholesterolbinding and transport, their biological significance seems to have adapted to serve specific functions critica...

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Section: Discussionmentioning

confidence: 99%

Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis

Fan

Rone

Papadopoulos

2009

Journal of Biological Chemistry

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“…Although the mechanism of diazepam-induced ROI generation was not resolved, some evidence suggests that the PBR could directly participate on oxidative metabolism. For example, the rat PBR can functionally replace a bacterial "oxygen sensor," 26 and a PBR-directed monoclonal antibody stimulated oxidative burst of human neutrophils, 27 suggestive for an involvement of PBR in ROI generation. NMDA-receptor activation and [Ca 2ϩ ] i elevation may be crucial for PTN in response to both ammonia 8 and diazepam (this paper).…”

Section: Discussionmentioning

confidence: 99%

Benzodiazepine-induced protein tyrosine nitration in rat astrocytes

Görg

2003

Hepatology

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Recent studies indicate that ammonia and hypoosmotic astrocyte swelling can induce protein tyrosine nitration (PTN) in astrocytes with potential pathogenetic relevance for hepatic encephalopathy (HE). Because HE episodes are known to be precipitated also by sedatives, the effects of benzodiazepines on PTN in cultured rat astrocytes and rat brain in vivo were studied. In cultured rat astrocytes, diazepam, PK11195, Ro5-4864, and the benzodiazepine binding inhibitor ( A strocytes are a major target of ammonia, with pathogenetic relevance for hepatic encephalopathy (HE) in acute and chronic liver failure. [1][2][3] Cerebral ammonia is eliminated by astrocytes, the predominant cellular compartment in the brain expressing glutamine synthetase. 4 Intracellular glutamine accumulation because of increased ammonia detoxification leads to astrocyte swelling, 5 which was recognized as an early pathogenic event already in subclinical HE in cirrhotic patients 6 and which may contribute to the severe rise in intracranial pressure in patients with fulminant hepatic failure. 7 Other lines of evidence point to a role of Nmethyl-D-aspartate (NMDA) receptors and nitric oxide (NO) in ammonia neurotoxicity. 7 As shown recently, ammonia increased protein tyrosine nitration (PTN) in cultured astrocytes, which depends on NMDA receptor activation, elevation of [Ca 2ϩ ] i , glutamine synthesis, and formation of NO and peroxynitrite. 8 PTN is also increased in brains from rats that underwent portocaval anastomosis or received an acute ammonia load, 8 suggesting a role of PTN in the pathogenesis of HE.Among the factors precipitating HE in cirrhotic patients, sedatives of the benzodiazepine type are well established. Two types of benzodiazepine receptors are known (reviewed in Zisterer and Williams 9 ). The peripheral-type benzodiazepine receptor (PBR) is in most cell types lo-

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“…Further, a monoclonal antibody raised against TSPO was able to dose-dependently and specifically enhance NOX2 activity (i.e., the oxidative burst) in neutrophils [29]. These studies suggested a TSPO-NOX2 interaction but this interaction was not investigated further.…”

Section: Tspo and Nadph Oxidase (Nox2) In Microgliamentioning

confidence: 99%

TSPO Finds NOX2 in Microglia for Redox Homeostasis

Guilarte

Loth

Guariglia

2016

Trends in Pharmacological Sciences

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During the past decade, Translocator Protein 18 kDa (TSPO), previously named peripheral benzodiazepine receptor, has gained a great deal of attention based on its use as a clinical biomarker of neuroinflammation with therapeutic potential. However, there is a paucity of knowledge on the function(s) of TSPO in glial cells. Here, we identify a novel function of TSPO in microglia that is not associated with steroidogenesis. We propose a TSPO interaction with NADPH Oxidase linking the generation of reactive oxygen species (ROS) signaling to the induction of an antioxidant response to maintain redox homeostasis. This line of investigation may provide a greater understanding of TSPO glial cell biology and the knowledge gained may prove beneficial in devising therapeutic strategies.

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A monoclonal antibody against peripheral benzodiazepine receptor activates the human neutrophil NADPH-oxidase

Cited by 24 publications

References 19 publications

Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis

Translocator Protein 2 Is Involved in Cholesterol Redistribution during Erythropoiesis

Benzodiazepine-induced protein tyrosine nitration in rat astrocytes

TSPO Finds NOX2 in Microglia for Redox Homeostasis

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