CD38/Cyclic ADP-Ribose Regulates Astrocyte Calcium Signaling: Implications for Neuroinflammation and HIV-1-Associated Dementia

Abstract

CD38 is a 45-kD ectoenzyme involved in the synthesis of potent calcium (Ca(2+))-mobilizing agents, cyclic adenosine diphosphate-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+). In HIV-1-infected patients, increased CD38 expression on CD8+ T cells is linked to immune system activation and progression of HIV-1 infection. However, the role of CD38 upregulation in astrocyte function and HIV-1-associated dementia (HAD-now called HAND: HIV-1-associated neurocognitive disorder) neuropathogenesis is unclear. To these ends, we used interleukin (IL)-1beta and HIV-1gp120 to activate primary human astrocytes and measured CD38 expression using real-time polymerase chain reaction and CD38 function by ADP-ribosyl cyclase activity. We also determined cADPR-mediated changes in single-cell intracellular Ca(2+) transients in activated astrocytes in presence or absence of ethylene glycol tetraacetic acid. CD38 levels were downregulated using CD38 small-interfering RNA (siRNA) and intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured. We previously reported a approximately 20-fold rise in CD38 messenger RNA levels in IL-1beta-activated astrocytes. We extend this observation and report that HIV-1gp120 potentiated CD38 expression in a dose-dependent manner and also increased CD38 enzyme activity in control and IL-1beta-activated astrocytes. We demonstrate higher cADPR levels in IL-1beta-activated astrocytes with a corresponding rise in [Ca(2+)](i) upon cADPR application and its non-hydrolysable analog, 3-deaza-cADPR. In activated astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca(2+)](i) to baseline, thus confirming a CD38-cADPR specific response. These data are important for unraveling the mechanisms underlying the role of astrocyte-CD38 in HAD and have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation.

CD20+ T cell numbers are decreased in untreated HIV-1 patients and recover after HAART

“…Lymphocyte populations are differently affected in HIV-1 infected patients, with decreased CD4 counts, altered NK cell phenotype [1], and increased CD38 in untreated patients [2,10]. Like CD38, CD20 is a cell surface molecule involved in Ca 2+ signalling [6,9]. Therefore, we investigated whether HIV-1 also affects the CD20 + T cell population in patients.…”

“…CD20 + T cells produce a variety of cytokines without prior activation but they exhibit less proliferative capacity and they are more prone to apoptosis than CD20 − T cells. CD38 is a 45-kDa ectoenzyme which is, among other things, involved in the synthesis of potent calcium (Ca 2+ )-mobilizing agents hence displaying functional similarities with CD20 [9]. CD38 is expressed on wide range of leukocytes with highest levels on activated T cells, plasma cells and other cells during proliferation.…”

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

“…Dramatic rise in CD38 messenger RNA levels in IL-1 -activated astrocytes was reported in HIV-associated neurodegeneration and dementia: in astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca 2+ ] i to baseline, thus confirming a CD38-cADPR specific response. These data have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation (Banerjee et al, 2008). We suggest that possible causes of elevation of CD38 expression in brain cells are the following: 1) changes in NAD + bioavailability (release from mitochondria into cytosol, cell death, connexin Cx43 activation); 2) redistribution of the enzyme in the cells; 3) cytokinedependent (IL, TNF) changes in expression of gene encoding for CD38 in the sites of brain injury of neurodegeneration; 4) action of neuro-and gliotransmitters.…”

Endothelial Progenitor Cells Physiology and Metabolic Plasticity in Brain Angiogenesis and Blood-Brain Barrier Modeling

“…In accordance with this metabolic pattern, we may propose that when BBB starts expression of GLUT for predominant consumption of glucose for NVU metabolic needs, glycolytic flux is activated as much as possible in BMEC, NAD+ is effectively regenerated due to pyruvate to lactate conversion, and NAD+ is easily used by NAD+-glycohydrolases or stimulates deacetylase activity. Probable involvement of NAD+-glycohydrolases (i.e., CD38) abundantly expressed in activated astroglial cells (Banerjee et al, 2008; Salmina et al, 2009) in the establishment of pro-angiogenic brain microenvironment might be suggested by analogy with the mechanism recently proposed in (Horenstein et al, 2015). …”