Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity

Liu, J; Xu, Changshui; Chen, L; Xu, Peng; Xiong, Huangui

doi:10.1038/cddis.2011.140

Cited by 43 publications

(47 citation statements)

References 40 publications

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“…Medders et al (2010) demonstrated that inhibition of p38 MAPK phosphorylation by a specific blocker prevents neuronal death in mixed neuronal-glial cultures. Recently, Liu et al (2012) have shown that phosphorylation of p38 MAPK is a requisite for induction of microglial neurotoxicity via enhancement of Kv1.3 current. Here we examined the time course of p-p38 MAPK expression after axotomy.…”

Section: Discussionmentioning

confidence: 99%

Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis

Yamada

Jinno

2013

J of Comparative Neurology

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A total of 136 microglia were intracellularly labeled and their morphological features were evaluated by 3D morphometric measurement. According to hierarchical cluster analysis, microglia were objectively categorized into four groups termed types I-IV. The validity of this classification was confirmed by principal component analysis and linear discriminant analysis. Type I microglia were found in sham-operated mice and in mice sacrificed 28 days (D28) after axotomy. The appearance of type I cells was similar to so-called ramified microglia in a resting state. Type II microglia were mainly seen in D14 mice, which exhibited small cell bodies with thin and short processes. Interestingly, none of the already-known morphological types of microglia seemed to be comparable to type II cells. We thus named type II microglia "small ramified" cells. Types III and IV microglia were mainly seen in D3 and D7 mice and their appearances were similar to hypertrophied and bushy cells, respectively. Proliferating cell nuclear antigen (PCNA), a mitosis marker, was almost exclusively expressed in D3 mice. On the other hand, voltage-dependent potassium channels (Kv1.3/1.5), neurotoxicity-related molecules, were most highly expressed in D14 mice. Increased expression of Kv1.3/1.5 in D14 mice was suppressed by minocycline treatment. These findings indicate that type II and III microglia may be involved in neurotoxicity and mitosis, respectively. Type IV microglial cells are assumed to be in the process of losing mitotic activity and gaining neurotoxicity. Our data also suggest that type II microglia can be a potential therapeutic target against neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis

Yamada

Jinno

2013

J of Comparative Neurology

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“…40 In in vitro studies, HIV gp120 activity unravels the involvement of p38 and resultant neurotoxic activity. 41,42 The signaling of p38 is critical upon exposure to HIV gp120 for the neurotoxic phenotype of monocytic cells. 43,44 HIV uses the p38 pathway to produce new viruses and to deplete CD4 + T cells from the host’s immune system.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 10 Mediated by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 in Rats

Zheng

Huang²,

et al. 2014

Anesthesia &Amp; Analgesia

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Background Human Immunodeficiency Virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model. Methods NP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing antiinflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves (AUC). The expression of phosphorylated p38 mitogen-activated kinase, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-1α), and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG) was examined at 14 and 28 days after vector inoculation using Western blots. Results We found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P<0.0001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted more than 28 days. The AUC in the HSV vector expressing IL-10 was increased compared with that in the control vector (P<0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-1α), and C-X-C chemokine receptor type 4 expression at 14 and/or 28 days in the DRG and/or the spinal dorsal horn. Conclusions Our studies demonstrate that blocking the signaling of these proinflammatory molecules in the DRG and/or the spinal cord using the HSV vector expressing IL-10 is able to reduce HIV-related NP. These results provide new insights on the potential mechanisms of HIV-associated NP and a proof-of concept for treating painful HIV sensory neuropathy with this type of gene therapy.

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“…Microglia and neurons were prepared from the cerebral cortex of postnatal 0–1 day old or 18-day old embryonic Sprague Dawley rats as described previously (Liu et al, 2012). In brief, rat cortical tissues were dissected in cold Hank’s Balanced Salt Solution (HBSS: Mediatech, Inc. Manassas, VA) and digested with 0.25% trypsin and 200 kunitz units/ml DNase (Sigma-Aldrich, St. Louis.…”

Section: Methodsmentioning

confidence: 99%

Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K + current

Liu

et al. 2017

Molecular and Cellular Neuroscience

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Methamphetamine (Meth) abuse not only increases the risk of human immunodeficiency virus-1 (HIV-1) infection, but exacerbates HIV-1-associated neurocognitive disorders (HAND) as well. The mechanisms underlying the co-morbid effect are not fully understood. Meth and HIV-1 each alone interacts with microglia and microglia express voltage-gated potassium (KV) channel KV1.3. To understand whether KV1.3 functions an intersecting point for Meth and HIV-1, we studied the augment effect of Meth on HIV-1 glycoprotein 120 (gp120)-induced neurotoxic activity in cultured rat microglial cells. While Meth and gp120 each alone at low (subtoxic) concentrations failed to trigger microglial neurotoxic activity, Meth potentiated gp120-induced microglial neurotoxicity when applied in combination. Meth enhances gp120 effect on microglia by enhancing microglial KV1.3 protein expression and KV1.3 current, leading to an increase of neurotoxin production and resultant neuronal injury. Pretreatment of microglia with a specific KV1.3 antagonist 5-(4-Phenoxybutoxy)psoralen (PAP) or a broad spectrum KV channel blocker 4-aminopyridine (4-AP) significantly attenuated Meth/gp120-treated microglial production of neurotoxins and resultant neuronal injury, indicating an involvement of KV1.3 in Meth/gp120-induced microglial neurotoxic activity. Meth/gp120 activated caspase-3 and increased caspase-3/7 activity in microglia and inhibition of caspase-3 by its specific inhibitor significantly decreased microglial production of TNF-α and iNOS and attenuated microglia-associated neurotoxic activity. Moreover, blockage of KV1.3 by specific blockers attenuated Meth/gp120 enhancement of caspase-3/7 activity. Taking together, these results suggest an involvement of microglial KV1.3 in the mediation of Meth/gp120 co-morbid effect on microglial neurotoxic activity via caspase-3 signaling.

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Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity

Cited by 43 publications

References 40 publications

Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis

Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis

Interleukin 10 Mediated by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 in Rats

Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K + current

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