MCP‐1 (CCL2) protects human neurons and astrocytes from NMDA or HIV‐tat‐induced apoptosis

Abstract

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu] e ) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu] e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.

MCP-1 and CCR2 Contribute to Non-Lymphocyte-Mediated Brain Disease Induced by Fr98 Polytropic Retrovirus Infection in Mice: Role for Astrocytes in Retroviral Neuropathogenesis

“…Many of these chemokines are also associated with neurological disease induced by other retroviruses including HIV and simian immunodeficiency virus (6,12,16,41). However, it was unclear if the upregulation of these chemokines was produced as a response to protect neurons, as has been suggested by some in vitro studies (7,15), or if the chemokines were responsible for mediating neuropathogenesis. To analyze the role of these chemokines in Fr98-mediated neurovirulence in vivo, we inoculated mice deficient in the chemokine receptors CCR2 or CCR5 with Fr98-infected NSC.…”

“…However, increased chemokine expression is observed in neurological diseases, such as human immunodeficiency virus (HIV)-associated dementia (6,16,39) and Alzheimer's disease (40), where lymphocytic cell infiltration in the brain does not correlate with pathogenesis (17,22). In these diseases, it is unclear whether chemokine upregulation is pathogenic or protective (7,12,15). Additionally, chemokine upregulation could simply be a response to pathogenesis rather than an active contributor or inhibitor of disease progression.…”

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

“…Liver cryosections (80 μm thick, to reconstruct the aggregates of inflammatory cells, from normal and LPS injected rats) or cultures of KCs plated on coverslips, were fixed and permeabilized in 70% ethanol for 20 min at −20°C, rinsed three times with PBS, and then incubated in blocking solution (5 mM EDTA, 1% fish gelatin, 1% BSA and 1% horse serum) for 30 min at room temperature according to a previous published protocols (11)(12)(13). Samples were then incubated in primary antibody (anti-Cx43, anti-ED2 or rabbit preimmune serum, 1:2000, 1:500 or 1:200, respectively) overnight at 4°C.…”

Immune Modulation in Glaucoma – Can Manipulation of Microglial Activation Help?

“…MCP-1/CCL2 is a β-chemokine involved in the activation and recruitment of monocytic cells to injury sites (Zhang and Koninck, 2006). MCP-1/CCL2 can either induce neuroprotection or neurodestruction depending on the experimental model (Galasso et al, 2000;Eugenin et al, 2003;Kalehua et al, 2004). Using MCP-1/CCL2, the activation states of microglia can be manipulated, they can exert divergent effects on RGC survival under COH.…”