In Vitro Downregulation of Matrix Metalloproteinase-9 in Rat Glial Cells by CCR5 Antagonist Maraviroc: Therapeutic Implication for HIV Brain Infection

Abstract

BackgroundMatrix metalloproteinases (MMPs) released by glial cells are important mediators of neuroinflammation and neurologic damage in HIV infection. The use of antiretroviral drugs able to combat the detrimental effect of chronic inflammation and target the exaggerated MMP activity might represent an attractive therapeutic challenge. Recent studies suggest that CCR5 antagonist maraviroc (MVC) exerts immunomodulant and anti-inflammatory activity beyond its anti-HIV properties. We investigated the in vitro effect of MVC on the activity of MMPs in astrocyte and microglia cultures.Methodology/Principal FindingsPrimary cultures of rat astrocytes and microglia were activated by exposure to phorbol myristate acetate (PMA) or lypopolysaccharide (LPS) and treated in vitro with MVC. Culture supernatants were subjected to gelatin zymography and quantitative determination of MMP-9 and MMP-2 was done by computerized scanning densitometry. MMP-9 levels were significantly elevated in culture supernatants from both LPS- and PMA-activated astrocytes and microglia in comparison to controls. The treatment with MVC significantly inhibited in a dose-dependent manner the levels and expression of MMP-9 in PMA-activated astrocytes (p<0,05) and, to a lesser extent, in PMA-activated microglia. By contrast, levels of MMP-2 did not significantly change, although a tendency to decrease was seen in PMA-activated astrocytes after treatment with MVC. The inhibition of levels and expression of MMP-9 in PMA-activated glial cells did not depend on cytotoxic effects of MVC. No inhibition of MMP-9 and MMP-2 were found in both LPS-activated astrocytes and microglia.ConclusionsThe present in vitro study suggests that CCR5 antagonist compounds, through their ability to inhibit MMP-9 expression and levels, might have a great potential for the treatment of HIV-associated neurologic damage.

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

“…MMP9 knockout reduces neuro-inflammation in experimental autoimmune encephalomyelitis (EAE) [11], while CSF MMP9 is elevated in patients with bacterial meningitis and BBB damage [12]. Moreover, inhibition of MMP9 alleviates the neurological damage associated with human immunodeficiency virus (HIV) infection [13], suggesting that MMP9 activation is a response to HIV infection. These data are also supported by enhanced expression and activity of MMP9 in serum, CSF, and demyelinating lesions in MS [14], and abundant evidence of increased MMP9 expression and activity in ischemic stroke [15, 16].…”

Matrix metalloproteinase levels in early HIV infection and relation to in vivo brain status

“…In chronic inflammation, all MMPs may be present (Ra and Parks, 2007). In vitro findings indicate MMP changes in response to antiretrovirals (Gramegna et al , 2011; Latronico et al , 2007), suggesting that MMPs may represent potential therapeutic targets. However, evidence of MMP physiologic significance in cognitive function underscores the necessity of further studies before MMPs are targeted for clinical intervention.…”

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

“…With regard to human immunodeficiency virus (HIV) infection, Gramegna et al . () found that the inhibition of MMP‐9 alleviated HIV‐associated neurological damage. Interestingly, Rumbaugh et al .…”