An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy

Lakritz, Jessica R.; Yalamanchili, Samshita; Polydefkis, Michael; Miller, Andrew D.; McGrath, Michael S.; Williams, Kenneth C.; Burdo, Tricia H.

doi:10.1007/s13365-017-0529-9

Cited by 6 publications

(3 citation statements)

References 41 publications

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“…Moreover, studies elucidating the role of monocytes/macrophages in SIV pathogenesis have indicated that monocyte/macrophage accumulation correlates with SIV disease severity and progression, tissue damage in the lung and gut, and SIV-associated encephalitis [ 61 – 63 ]. Importantly, inhibiting macrophage accumulation has shown therapeutic benefits in models of both liver disease and SIV infection [ 36 , 38 , 39 , 64 , 65 ]. In our study, we observed an increase in hepatic monocyte/macrophages during SIV infection that correlated with both inflammatory (TNFα, CCL3) and fibrosis (TGFβ) mediators suggesting multiple, and maybe even opposing, roles during infection.…”

Section: Discussionmentioning

confidence: 99%

Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

et al. 2018

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Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFβ). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.

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Section: Discussionmentioning

confidence: 99%

Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

et al. 2018

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“…In a simian immunodeficiency virus encephalopathy (SIVE) model wherein OPN expression in brain macrophages contributes to AIDS dementia pathogenesis, MGBG inhibits expression of OPN and SIV p28 expression within the brain, and appears moderately effective in preventing the macaques from developing SIVE [ 71 ]. MGBG also reduces monocyte activation, the dorsal root ganglia pathology, and inflammation in the SIVE model [ 72 ]. In this model, SIV infected macaques also developed myocarditis and early atherosclerosis, processes independent of the presence of infected cells within diseased tissues.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal-bis-guanylhydrazone inhibits osteopontin expression and differentiation in cultured human monocytes

Jin

McGrath

2018

PLoS ONE

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Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 μM of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.

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“…Plasma SIV-RNA was quantified using real-time PCR for all animals used in this study, as previously described. 44 The threshold sensitivity was 15 copy Eq/mL, with an average interassay %CV of <25%.…”

Section: Viral Load Measurementmentioning

confidence: 97%

Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection

Robinson

Guenthner

Warfield

et al. 2020

The American Journal of Pathology

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HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the posteantiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B 4 isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4 þ and tropomyosin receptor kinase Aepositive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4 þ nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.

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An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy

Cited by 6 publications

References 41 publications

Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

Liver macrophage-associated inflammation correlates with SIV burden and is substantially reduced following cART

Methylglyoxal-bis-guanylhydrazone inhibits osteopontin expression and differentiation in cultured human monocytes

Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection

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