CD38 regulation in activated astrocytes: Implications for neuroinflammation and HIV‐1 brain infection

Abstract

Reactive astrogliosis is a key pathological aspect of neuroinflammatory disorders including human immunodeficiency virus type 1 (HIV-1)-associated neurological disease. On the basis of previous data that showedastrocytes activated with interleukin (IL)-1beta induce neuronal injury, we analyzed global gene changes in IL-1beta-activated human astrocytes by gene microarray. Among the up-regulated genes, CD38, a 45-kDa type II single chain transmembrane glycoprotein, was a top candidate, with a 17.24-fold change that was validated by real-time polymerase chain reaction. Key functions of CD38 include enzymatic activities and involvement in adhesion and cell signaling. Importantly, CD38(+)CD8(+) T-cell expression is a clinical correlate for progression of HIV-1 infection and biological marker for immune activation. Thus, CD38 expression in HIV-1 and/or IL-1beta-stimulated human astrocytes and human brain tissues was analyzed. IL-1beta and HIV-1 activation of astrocytes enhanced CD38 mRNA levels. Both CD38 immunoreactivity and adenosine 5'-diphosphate (ADP)-ribosyl cyclase activity were up-regulated in IL-1beta-activated astrocytes. CD38 knockdown using specific siRNAs significantly reduced astrocyte proinflammatory cytokine and chemokine production. However, CD38 mRNA levels were unchanged in IL-1beta knockdown conditions, suggesting that IL-1beta autocrine loop is not implicated in this process. Quantitative immunohistochemical analysis of HIV-seropositive without encephalitis and HIV-1 encephalitis brain tissues showed significant up-regulation of CD38, which colocalized with glial fibrillary acidic protein-positive cells in areas of inflammation. These results suggest an important role of CD38 in the regulation of astrocyte dysfunction during the neuroinflammatory processes involved in neurodegenerative/neuroinflammatory disorders such as HIV-1 encephalitis.

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Microglia and astrocytes maintain homeostasis within the CNS during health; however, they also mediate very specific disease mechanisms as illustrated in Alexander's disease in which GFAP polymorphisms result in demyelination, neurodegeneration, and delayed development (56,57) or HIV-associated encephalopathy during which microglia/macrophages and astrocytes are infected by HIV-1, resulting in neuroinflammation with axonal loss (58,59). Hence it is plausible that a retroviral env-encoded glycoprotein such as Syncytin-1 might induce ER stress and inflammation in glia, which results in impaired myelin homeostasis and limited remyelination postinjury.…”

Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling

“…Both connexin and nucleoside transporters are also present in the organellar membranes and can perform similar functions for the type-II CD38 that is intracellular (reviewed in [138,139]). Indeed, it is well documented that CD38 is, by no means, a purely surface protein, but is expressed also in organelles [144][145][146], including the nucleus [147][148][149].…”

Astrocyte CD38: Links to Neuroinflammation in HAND

“…IL-1-activated astrocytes are known to release cytokines like IL-6 and chemokines like CCL2, CXCL8 and RANTES (Lee and Aarhus, 1993;Zhao and Brinton, 2004;Sharma et al, 2007). Our work showed that CD38 is a partial regulator of chemokine and cytokine signaling by IL-1-activated astrocytes, thus affecting the inflammatory milieu during HIVE (Kou et al, 2009). IL-1 has also been shown to mediate activation of mitogen activated protein kinases (MAPKs) in primary astrocyte cultures (Parker et al, 2002;.…”

“…Our previous work showed IL-1-mediated astrocyte Fas ligand expression and subsequent caspase activation in surrounding neurons in vitro (Deshpande et al, 2005). We have also shown the effects of IL-1 and HIV-1 gp120, leading to CD38 upregulation in primary astrocyte cultures (Banerjee et al, 2008) and increased CD38 mRNA and protein expression in HIVE brain (Kou et al, 2009). IL-1-activated astrocytes are known to release cytokines like IL-6 and chemokines like CCL2, CXCL8 and RANTES (Lee and Aarhus, 1993;Zhao and Brinton, 2004;Sharma et al, 2007).…”

“…A paracrine model of interaction has been suggested, involving NAADP+ and cADPR, leading to glutamate-release by astrocytes, affecting neurons (Verderio et al, 2001;De Flora et al, 2004). Our previous data demonstrate that in HIV-1 CNS disease, astrocytes express elevated levels of CD38 (Kou et al, 2009), thus activating these paracrine pathways. The possible connections between HIV-1 infection, neuroinflammation and astrocyte activation, which result in CD38 upregulation and dysregulation of Ca 2+ /glutamate homeostasis and culminate in neuronal injury (Fig.…”