HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system

Guedia, Joy; Brun, Paola; Bhave, Sukhada; Fitting, Sylvia; Kang, Minho; Dewey, William L.; Hauser, Kurt F.; Akbarali, Hamid I.

doi:10.1038/srep31203

Cited by 18 publications

(14 citation statements)

References 47 publications

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“…6A , B). A different profile was observed with TNFα, where short‐term LPS exposure (1 h) did not alter TNFα mRNA expression, but upregulation was seen after 16 h exposure (16) (Fig. 6 C ).…”

Section: Resultsmentioning

confidence: 81%

“…Systemic acute LPS activates glial fibrillary acidic protein (GFAP)‐expressing myenteric glia (15), resulting in the secretion of increased levels of proinflammatory cytokines. Similarly, LPS‐induced cytokine release in the myenteric glia is synergistically enhanced by the viral protein HIV‐1 Tat (16), thus highlighting the significance of glia‐mediated immune responses in the ENS. In an immune‐stimulated environment, enteric glia serve as an important source of inflammatory mediators, including cytokines, ATP, NO, and reactive oxygen species.…”

mentioning

confidence: 99%

“…Systemic acute LPS activates glial fibrillary acidic protein (GFAP)-expressing myenteric glia (15), resulting in the secretion of increased levels of proinflammatory cytokines. Similarly, LPS-induced cytokine release in the myenteric glia is synergistically enhanced by the viral ABBREVIATIONS: mOR, m-opioid receptor; CBX, carbenoxolone; Cx43, connexin-43; ENS, enteric nervous system; FBS, fetal bovine serum; GFAP, glial fibrillary acidic protein; GI, gastrointestinal; H&E, hematoxylin and eosin; I Kdr , delayed-rectifier potassium current; IBD, inflammatory bowel disease; K ir , inwardly rectifying potassium; LMMP, longitudinal muscle myenteric plexus; PPADS, pyridoxalphosphate-6-azophenyl-29,49-disulfonic acid; RMP, resting membrane potential; SW, Swiss Webster; TEA, tetraethylammonium; TNBS, trinitrobenzene sulfonic acid protein HIV-1 Tat (16), thus highlighting the significance of glia-mediated immune responses in the ENS. In an immune-stimulated environment, enteric glia serve as an important source of inflammatory mediators, including cytokines, ATP, NO, and reactive oxygen species.…”

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confidence: 99%

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Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

et al. 2017

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Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance, limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut, predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment () but not upon direct exposure of glia to morphine (). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1β mRNA in enteric glia. LPS increased connexin43 (Cx43) expression and enhanced ATP release from enteric glia cells. LPS-induced P2X currents and proinflammatory cytokine mRNA expression were blocked by the Cx43 blockers Gap26 and carbenoxolone. Likewise, colonic inflammation related to prolonged exposure to morphine was significantly attenuated by carbenoxolone (25 mg/kg). Carbenoxolone also prevented gut wall disruption and significantly reduced morphine-induced constipation. These findings imply that enteric glia activation is a significant modulator of morphine-related inflammation and constipation.-Bhave, S., Gade, A., Kang, M., Hauser, K. F., Dewey, W. L., Akbarali, H. I. Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.

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Section: Resultsmentioning

confidence: 81%

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confidence: 99%

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confidence: 99%

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Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

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“…In addition to inducing Tat mRNA expression in GFAP+ brain astroglia, Tat mRNA is also induced in GFAP+ myenteric glia within 72 h, and reduces gut microbiota 82 . If doxycycline is withheld, Tat continues to be expressed at 3 weeks and commensal gut bacteria recolonize within 2 weeks 83 . Upon microbial recolonization in the absence of doxycycline, Tat heightens gut-barrier leakiness resulting in increased levels of serum LPS, proinflammatory cytokines in the gut, and bacteria in the mesenteric lymph nodes, spleen, and liver 83 , which could potentially influence peripheral immune response, CNS pathology and function 84 .…”

Section: Discussionmentioning

confidence: 99%

“…If doxycycline is withheld, Tat continues to be expressed at 3 weeks and commensal gut bacteria recolonize within 2 weeks 83 . Upon microbial recolonization in the absence of doxycycline, Tat heightens gut-barrier leakiness resulting in increased levels of serum LPS, proinflammatory cytokines in the gut, and bacteria in the mesenteric lymph nodes, spleen, and liver 83 , which could potentially influence peripheral immune response, CNS pathology and function 84 . The interactions of HIV-Tat with gut epithelia, immune/inflammatory responses, and effects on CNS function warrant further consideration.…”

Section: Discussionmentioning

confidence: 99%

Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging

Dickens

Yoo

Chin

et al. 2017

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The widespread use of combinational antiretroviral therapies (cART) in developed countries has changed the course of Human Immunodeficiency Virus (HIV) infection from an almost universally fatal disease to a chronic infection for the majority of individuals. Although cART has reduced the severity of neurological damage in HIV-infected individuals, the likelihood of cognitive impairment increases with age, and duration of infection. As cART does not suppress the expression of HIV non-structural proteins, it has been proposed that a constitutive production of HIV regulatory proteins in infected brain cells may contribute to neurological damage. However, this assumption has never been experimentally tested. Here we take advantage of the leaky tetracycline promoter system in the Tat-transgenic mouse to show that a chronic very low-level expression of Tat is associated with astrocyte activation, inflammatory cytokine expression, ceramide accumulation, reductions in brain volume, synaptic, and axonal damage that occurs over a time frame of 1 year. These data suggest that a chronic low-level production of Tat may contribute to progressive neurological damage in virally suppressed HIV-infected individuals.

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The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats

et al. 2018

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Human immunodeficiency virus type 1 (HIV-1) affects the central nervous system (CNS) that may lead to the development of HIV-associated neuropathologies. Tat protein is one of the viral proteins that have been linked to the neurotoxic effects of HIV. Since many individuals living with HIV often experience significant adverse circumstances, the present study investigated whether exposure to stressful conditions would exacerbate harmful effects of tat protein on brain function. Tat protein (10 μg/10 μl) was injected bilaterally into the dorsal hippocampus of the animal using stereotaxic techniques. The control group received an injection of saline (10 μl). Some control and tat protein-treated animals were subjected to restrain stress for 6 h per day for 28 days and compared to a non-stress group. All animals underwent two behavioural tests, the open field test (OFT) and the novel object recognition test (NORT) to assess their mood state and cognitive function respectively. The release of pro-inflammatory cytokines (TNF-α and IL-1β) and the expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were also measured to see whether the impact of the repetitive stress on Tat protein-induced behavioural effects was mediated by elements of the immune system and the HPA axis. Rats treated with tat protein showed the following behavioural changes when compared to control animals: there was a significant decrease in time spent in the center of the open field during the OFT, a significant reduction in time spent with the novel object during the NORT, but no change in locomotor activity. Real-time PCR data showed that the expression levels of GR and MR mRNA were significantly reduced, while Western blot analysis showed that the protein expression levels of TNF-α and IL-1β were significantly increased. The present findings indicated that injection of tat protein into the hippocampus of rats not subjected to stress may lead to anxiety-like behaviour and deficits in learning and memory. Tat-treated animals subjected to stress evoked only a modest effect on their behaviour and neurochemistry, while stress alone led to behavioural and neurochemical changes similar to tat protein.

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HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system

Cited by 18 publications

References 47 publications

Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

Connexin‐purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation

Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging

The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats

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