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Localization of TGF-O peptide and HIV-1 RNA in AIDS brain tissues. Immunocytochemical staining for TGF-O in (A) perivascular regions (original magnification, x 32) ; (B) multinucleated giant cells (original magnification, x 250) and (C) vacuolated phagocytic cells (original magnification, x 250). (D) In situ hybridization for HIV-1 mRNA. Sections of brain tissue from patient 3 stained with TGFLO (E) and GFAP (F) (original magnification, x 32) .
Source publication
The multifunctional cytokine, transforming growth factor beta (TGF-beta), was identified by immunocytochemistry in the brain tissues of four patients with acquired immune deficiency syndrome (AIDS), but not in control brain tissue. The TGF-beta staining was localized to cells of monocytic lineage as well as astrocytes, especially in areas of brain...
Citations
... 15,69 Upon stimulation, astrocytes secrete inflammatory cytokines that act in autocrine and paracrine manners. 70,71 Reactive astrocytes also express adhesion molecules and chemokines that influence blood-brain barrier permeability and the passage of immune cells from the periphery into the brain. 72 Unchecked, the inflammatory cycle may lead to neurodegeneration. ...
Background:
Alterations of astrocyte function play a crucial role in neuroinflammatory diseases due to either the loss of their neuroprotective role or the gain of their toxic inflammatory properties. Accumulating evidence highlights that cannabinoids and cannabinoid receptor agonists, such as WIN55,212-2 (WIN), reduce inflammation in cellular and animal models. Thus, the endocannabinoid system has become an attractive target to attenuate chronic inflammation in neurodegenerative diseases. However, the mechanism of action of WIN in astrocytes remains poorly understood.
Objective:
We studied the immunosuppressive property of WIN by examining gene expression patterns that were modulated by WIN in reactive astrocytes.
Materials and Methods:
Transcriptomic analysis by RNA-seq was carried out using primary human astrocyte cultures stimulated by the proinflammatory cytokine interleukin 1 beta (IL1β) in the presence or absence of WIN. Real-time quantitative polymerase chain reaction analysis was conducted on selected transcripts to characterize the dose-response effects of WIN, and to test the effect of selective antagonists of cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptors (PPAR).
Results:
Transcriptomic analysis showed that the IL1β-induced inflammatory response is robustly inhibited by WIN pretreatment. WIN treatment alone also induced substantial gene expression changes. Pathway analysis revealed that the anti-inflammatory properties of WIN were linked to the regulation of kinase pathways and gene targets of neuroprotective transcription factors, including PPAR and SMAD (mothers against decapentaplegic homolog). The inhibitory effect of WIN was dose-dependent, but it was not affected by selective antagonists of CB1 or PPAR.
Conclusions:
This study suggests that targeting the endocannabinoid system may be a promising strategy to disrupt inflammatory pathways in reactive astrocytes. The anti-inflammatory activity of WIN is independent of CB1, suggesting that alternative receptors mediate the effects of WIN. These results provide mechanistic insights into the anti-inflammatory activity of WIN and highlight that astrocytes are a potential therapeutic target to ameliorate neuroinflammation in the brain.
... While microglia have been shown to be capable of supporting HIV-1 replication in the CNS, the effects observed after microglial exposure to extracellular Tat have also suggested that infection was not required to elicit microglial activation and neurotoxic activities [74,75]. Microglial activation was typically characterized by cytokine production and synthesis of ROS ( Fig. 3) [76,77]. ...
Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) is a potent mediator involved in the development of HIV-1-associated neurocognitive disorders (HAND). Tat is expressed even in the presence of antiretroviral therapy (ART) and is able to enter the central nervous system (CNS) through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. The presence of low concentrations of extracellular Tat alone has been shown to lead to dysregulated gene expression, chronic cell activation, inflammation, neurotoxicity, and structural damage in the brain. The reported effects of Tat are dependent in part on the specific HIV-1 subtype and amino acid length of Tat used. HIV-1 subtype B Tat is the most common subtype in North American and therefore, most studies have been focused on subtype B Tat; however, studies have shown many genetic, biologic, and pathologic differences between HIV subtype B and subtype C Tat. This review will focus primarily on subtype B Tat where the full-length protein is 101 amino acids, but will also consider variants of Tat, such as Tat 72 and Tat 86, that have been reported to exhibit a number of distinctive activities with respect to mediating CNS damage and neurotoxicity.
... On the one hand, the cytokine was shown to produce protective effects against neurodegenerative changes induced by ischemia [20] and Alzheimer's disease [21,22]. On the other hand, it was reported that TGF-β1 is involved in the formation of plaques [23] and that its expression is associated with pathological processes [24]. TGF-β1 is involved in some forms of synaptic plasticity [25][26][27][28][29]. ...
The effect of the anti-inflammatory cytokine IL-10 on the ultrastructural distribution of AMPA receptor GluR1 subunit in CA1 field of cultured hippocampal slices was studied by using immunohistochemical technique. It was found that long-term posttetanic potentiation increased the content of GluR1 in the postsynaptic density of the axo-spinous synapse. Addition of IL-10 in concentrations of 1 and 10 ng/ml to the medium facilitated long-term posttetanic potentiation thereby changing the distribution of GluR1 in the spine: the number of receptors increased in the cytoplasm and decreased in the postsynaptic density. It is assumed that activation of neuronal IL-10 receptors affects the distribution of AMPA receptors in axo-spinous synapses of hippocampal field CA1 through interplay of intracellular signaling pathways, thereby participating in the mechanisms of synaptic plasticity under normal conditions.
... These pathways themselves may be influenced by ART. For example, the nuclear signaling adapter protein TRAF6 regulates both systems [20], and signaling through TAK1/MKK3/p38 includes proinflammatory cytokines that are elevated in HIV infection and induce TGF-β1 [21,22]. But TRAF6 function is modulated by immunoproteasome degradation. ...
Human immunodeficiency virus (HIV) infection is an independent risk factor for cardiovascular disease. This risk is magnified by certain antiretrovirals, particularly the protease inhibitor ritonavir, but the pathophysiology of this connection is unknown. We postulated that a major mechanism for antiretroviral-associated cardiac disease is pathologic fibrosis linked to platelet activation with release and activation of transforming growth factor (TGF)-β1, and that these changes could be modeled in a murine system. We also sought to intervene utilizing inhaled carbon monoxide (CO) as proof-of-concept for therapeutics capable of regulating TGF-β1 signaling and collagen autophagy. We demonstrate decreased cardiac function indices, including cardiac output, ejection fraction and stroke volume, and prominent cardiac fibrosis, in mice exposed to pharmacological doses of ritonavir. Cardiac output and fibrosis correlated with plasma TGF-β1 levels. Mice with targeted deletion of TGF-β1 in megakaryocytes/platelets (PF4CreTgfb1flox/flox) were partially protected from ritonavir-induced cardiac dysfunction and fibrosis. Inhalation of low dose CO (250ppm), used as a surrogate for upregulation of inducible heme oxygenase/endogenous CO pathways, suppressed ritonavir-induced cardiac fibrosis. This occurred in association with modulation of canonical (Smad2) and non-canonical (p38) TGF-β1 signaling pathways. In addition, CO treatment suppressed the M1 pro-inflammatory subset of macrophages and increased M2c regulatory cells in the hearts of RTV-exposed animals. The effects of CO were dependent upon autophagy as CO did not mitigate ritonavir-induced fibrosis in autophagy-deficient LC3-/- mice. These results suggest that platelet-derived TGF-β1 contributes to ritonavir-associated cardiac dysfunction and fibrosis, extending the relevance of our findings to other antiretrovirals that also activate platelets. The anti-fibrotic effects of CO are linked to alterations in TGF-β1 signaling and autophagy, suggesting a proof-of-concept for novel interventions in HIV/antiretroviral therapy-mediated cardiovascular disease.
... TGF-b1 expression is also increased in HIVinfected patients and correlates with disease progression ( Lotz and Seth 1993;Wiercinska- Drapalo et al. 2004). HIV tat protein has been linked to high TGF-b secretion in infected cells ( Wahl et al. 1991;Zauli et al. 1992;Lotz et al. 1994;Sawaya et al. 1998;Reinhold et al. 1999). The association of viral gp160 with CD4 on monocytes can also induce TGF-b production ( Hu et al. 1996). ...
Transforming growth factor β (TGF-β) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-β alters immunity under various conditions. Under steady-state conditions, TGF-β regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-β inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral (p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-β controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-β plays a pivotal role in maintaining peripheral tolerance against self- and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.
... In addition to HIV's primary cytotoxic effects on helper T cells, HIV-associated immunodeficiency can be mediated by the overexpression of transforming growth factor beta (TGFβ) by infected macrophages in the brains of HIV-infected patients. TGF-β2 is a cytokine with immunosuppressive effects and is detected in the brains of HIV-infected patients, but not in uninfected individuals [13,50]. Similarly, TGF-β2 is overexpressed in many astrocytomas and in glioblastoma, but not in normal brain [13]. ...
Background
Improvement in antiviral therapies have been accompanied by an increased frequency of non-Acquired Immune Deficiency Syndrome (AIDS) defining malignancies, such as glioblastoma multiforme. Here, we investigated all reported cases of human immunodeficiency virus (HIV)-positive patients with glioblastoma and evaluated their clinical outcomes. A comprehensive review of the molecular pathogenetic mechanisms underlying glioblastoma development in the setting of HIV/AIDS is provided.
Methods
We performed a PubMed search using keywords “HIV glioma” AND “glioblastoma,” and “AIDS glioma” AND “glioblastoma.” Case reports and series describing HIV-positive patients with glioblastoma (histologically-proven World Health Organization grade IV astrocytoma) and reporting on HAART treatment status, clinical follow-up, and overall survival (OS), were included for the purposes of quantitative synthesis. Patients without clinical follow-up data or OS were excluded. Remaining articles were assessed for data extraction eligibility.
Results
A total of 17 patients met our inclusion criteria. Of these patients, 14 (82.4%) were male and 3 (17.6%) were female, with a mean age of 39.5±9.2 years (range 19–60 years). Average CD4 count at diagnosis of glioblastoma was 358.9±193.4 cells/mm³. Tumor progression rather than AIDS-associated complications dictated patient survival. There was a trend towards increased median survival with HAART treatment (12.0 vs 7.5 months, p=0.10)
Conclusion
Our data suggests that HAART is associated with improved survival in patients with HIV-associated glioblastoma, although the precise mechanisms underlying this improvement remain unclear.
... Mesangial cells have been reported to contribute to the elevated production of TGF-β in the kidneys of HIV-infected individuals [23,24]. Peripheral blood mononuclear cells have also been found to produce and secrete TGF-β, with associated elevation of TGF-β in the plasma and tissues [37,38,[66][67][68][69]. Thus, monocytes/macrophages infected with HIV may also contribute to the local production of TGF-β in the kidneys. ...
Objective:
High rates of albuminuria are observed among HIV-infected individuals on stable antiretroviral therapy (ART). Though pro-inflammatory and pro-fibrotic responses are described as components of albuminuria in the general population, it is unclear how these responses are associated to albuminuria in ART-treated chronic HIV. We investigated the relationship of monocyte subsets and urine inflammatory and fibrotic biomarkers to albuminuria in ART-treated HIV-infected participants.
Design and methods:
Cross-sectional analyses were performed on Hawaii Aging with HIV-cardiovascular disease study cohort participants who were required at entry to be ≥40 years old and on ART ≥3 months. Monocyte subpopulations were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow-cytometry. Entry random urine samples were assessed for albumin-to-creatinine ratios (UACR). Urine samples were measured for inflammatory and fibrotic biomarkers using Luminex technology.
Results:
Among 96 HIV-infected subjects with measured UACR (87% male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/μL), 18 patients (19%) had albuminuria. Non-classical (CD14low/+CD16++) monocytes were significantly elevated in subjects with albuminuria (p = 0.034) and were correlated to UACR (r = 0.238, p = 0.019). Elevated non-classical monocyte counts were significant predictors of worsening albuminuria, independent of traditional- and ART-associated risk factors (β = 0.539, p = 0.007). Urine TGF-β1 and collagen-IV were significantly higher in albuminuric compared to non-albuminuric participants (TGF-β1; p = 0.039 and collagen-IV; p = 0.042). Urine TGF-β1 was significantly correlated with non-classical monocyte counts (r = 0.464, p = 0.017).
Conclusion:
Alterations in monocyte subpopulations and urine pro-fibrotic factors may play a role in kidney dysfunction during chronic HIV infection and warrants further study.
... Under physiologic conditions (Fig. 1A), collagen synthesis is controlled by two distinct TGF-β signaling pathways, Smad and TAK1/MKK3/p38 [28]. TRAF6 regulates both canonical Smad pathways via cytokines that are elevated in HIV infection and induce TGF-β1 [29], and Smad-independent pathways involving TAK1/MKK3/p38 [30]. The latter includes a negative feedback loop involving Beclin 1. Beclin 1 is involved in autophagydependent collagen degradation in cardiac tissues [31]. ...
... As noted above, we demonstrated that RTV enhanced RANKL signaling via inhibition of TRAF6 degradation in the immunoproteasome [6,13,14], resulting in increased monocyte differentiation into boneresorbing osteoclasts [11]. TRAF6 also mediates TGF-β1 signaling [29][30][31], so that in our opinion RTV should facilitate TGF-β activity in a manner similar to RANKL. Cytokines apart from TGF-β1 that are involved in cardiac fibrosis, including IL-13 [41], also signal via TRAF6 [42] and may be similarly enhanced by RTV. ...
HIV infection elevates the incidence of cardiovascular disease (CVD) independent of traditional risk factors. Autopsy series document cardiac inflammation and endomyocardial fibrosis in the HIV+ treatment naïve, and gadolinium enhancement magnetic resonance imaging has identified prominent myocardial fibrosis in the majority of HIV+ individuals despite use of suppressive antiretroviral therapies (ART). The extent of such disease may correlate with specific ART regimens. For example, HIV-infected patients receiving ritonavir (RTV)-boosted protease inhibitors have the highest prevalence of CVD, and RTV-exposed rodents exhibit cardiac dysfunction coupled with cardiac and vascular fibrosis, independent of RTV-mediated lipid alterations. We recently showed that platelet transforming growth factor (TGF)-β1 is a key contributor to cardiac fibrosis in murine models. We hypothesize that in the HIV+/ART naïve, cardiac fibrosis is a consequence of proinflammatory cytokine and/or ART-linked platelet activation with release of TGF-β1. Resultant TGF-β1/Smad signaling would promote collagen synthesis and organ fibrosis. We document these changes in a pilot immunohistochemical evaluation of cardiac tissue from two ART-naive pediatric AIDS patients. In terms of ART, we showed that RTV inhibits immunoproteasome degradation of TRAF6, a nuclear adapter signaling molecule critical to the regulation of proinflammatory cytokine signaling pathways involved in osteoclast differentiation and accelerated osteoporosis. We now present a model illustrating how RTV could similarly amplify TGF-β1 signaling in the promotion of cardiac fibrosis and accelerated CVD. Supportive clinical data correlate RTV use with elevation of NT-proBNP, a biomarker for CVD. We discuss potential interventions involving intrinsic modulators of inflammation and collagen degradation, including carbon monoxide-based therapeutics.
... Excitotoxicity is a direct result of abnormal regulation of glutamate concentrations in the synapse. As a common neurotoxic mechanism, excitotoxicity is implicated in many neurodegenerative conditions including HAND and METH Hori et al., 1999 Increased TGF-β1 Tat treatment and expression Wahl et al., 1991;Cupp et al., 1993;Rasty et al., 1996;Thatikunta et al., 1997 Decreased IL-1β-induced TIMP-1 and MMP-2 expression, increased ECM levels abuse Jaiswal et al., 2009;Vázquez-Santiago et al., 2014). During physiologic glutamatergic signaling, glutamate interacts with its receptors, N-methyl-D-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPA), to induce a Ca 2+ influx and potentiation of the excitatory signal. ...
As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. While METH abuse is common in the general population, between 10 and 15% of human immunodeficiency virus-1 (HIV-1) patients report having abused METH. METH exacerbates the severity and onset of HIV-1-associated neurocognitive disorders (HAND) through direct and indirect mechanisms. Repetitive METH use impedes adherence to antiretroviral drug regimens, increasing the likelihood of HIV-1 disease progression toward AIDS. METH exposure also directly affects both innate and adaptive immunity, altering lymphocyte numbers and activity, cytokine signaling, phagocytic function and infiltration through the blood brain barrier. Further, METH triggers the dopamine reward pathway and leads to impaired neuronal activity and direct toxicity. Concurrently, METH and HIV-1 alter the neuroimmune balance and induce neuroinflammation, which modulates a wide range of brain functions including neuronal signaling and activity, glial activation, viral infection, oxidative stress, and excitotoxicity. Pathologically, reactive gliosis is a hallmark of both HIV-1- and METH-associated neuroinflammation. Significant commonality exists in the neurotoxic mechanisms for both METH and HAND; however, the pathways dysregulated in astroglia during METH exposure are less clear. Thus, this review highlights alterations in astrocyte intracellular signaling pathways, gene expression and function during METH and HIV-1 comorbidity, with special emphasis on HAND-associated neuroinflammation. Importantly, this review carefully evaluates interventions targeting astrocytes in HAND and METH as potential novel therapeutic approaches. This comprehensive overview indicates, without a doubt, that during HIV-1 infection and METH abuse, a complex dialog between all neural cells is orchestrated through astrocyte regulated neuroinflammation.
... Previous studies indicated that astrocytes can also produce IL-2 both in vitro and in vivo [22][23][24][25]. Moreover, previous research showed that astrocytes can produce transforming growth factor-β (TGF-β) [26,27], a potent Foxp3-inducing cytokine. Since STAT5 is critical for the IL-2 signal pathway, we firstly used a STAT5 inhibitor and/or TGF-β RI kinase inhibitor VI (SB431542) in the co-culture to block the STAT5 and/or TGF-β signaling. ...
Forkhead box P3 (Foxp3)(+) regulatory T (Treg) cells maintain the immune tolerance and prevent inflammatory responses in the periphery. However, the presence of Treg cells in the central nervous system under steady state has not been studied. Here, for the first time, we show a substantial TCRαβ (+) CD4(+) Foxp3(+) T-cell population (cerebral Treg cells) in the normal rat cerebrum, constituting more than 15% of the cerebral CD4(+) T-cell compartment. Cerebral Treg cells showed an activated/memory phenotype and expressed many Treg-cell signature genes at higher levels than peripheral Treg cells. Consistent with their activated/memory phenotype, cerebral Treg cells robustly restrained the LPS-induced inflammatory responses of brain microglia/macrophages, suggesting a role in maintaining the cerebral homeostasis by inhibiting the neuroinflammation. In addition, brain astrocytes were the helper cells that sustained Foxp3 expression in Treg cells through IL-2/STAT5 signaling, showing that the interaction between astrocytes and Treg cells contributes to the maintenance of Treg-cell identity in the brain. Taken together, our work represents the first study to characterize the phenotypic and functional features of Treg cells in the normal rat cerebrum. Our data have provided a novel insight for the contribution of Treg cells to the immunosurveillance and immunomodulation in the cerebrum under steady state. This article is protected by copyright. All rights reserved.
