Astrocytes contacting HIV‐1‐infected macrophages increase the release of CCL2 in response to the HIV‐1‐dependent enhancement of membrane‐associated TNFα in macrophages

Abstract

The presence of human immunodeficiency virus (HIV)-infected macrophages in the parenchyma of central nervous system is an hallmark of acquired immunodeficiency syndrome-related neuroinflammation. Once penetrated the blood-brain barrier (BBB), macrophages closely interact with astrocytes, beginning with those lying beneath the BBB endothelium. By investigating the consequences of the cell-cell interaction between HIV-infected macrophages and astrocytes, we observed that the HIV-1 expression in macrophagic cells correlated with increased chemotactic activity in supernatants of astroglial cells. Gene array analysis revealed an impressive increase in the transcription of the gene for the CCL2/MCP-1 chemokine in astroglial cells isolated from HIV-1-infected co-cultures compared with cells from uninfected co-cultures. This phenomenon coupled with the increase in CCL2 release and depended on the cell-cell contact. In addition, it was a consequence of the HIV-1-induced enhancement of membrane-associated tumor necrosis factor-α in macrophagic cells, and correlated with increased levels of nuclear factor kappaB activation in astroglial cells. These observations could mirror a mechanism of recruitment of leukocytes through the BBB, likely contributing to the increase in both viral load and inflammation in central nervous system of HIV-infected patients.

Immuno-Pharmacological Targeting of Virus-Containing Compartments in HIV-1-Infected Macrophages

“…Of particular interest for the present article, CCL2 (a CC chemokine binding to CCR2) was found to be significantly elevated in the CSF of AIDS patients affected by encephalitis caused either by either HIV-1 or by cytomegalovirus, but not by other opportunistic infections or tumors of the CNS [52,53]. Similar evidence has been obtained in macaques infected with simian immunodeficiency virus (SIV) in which a major source of CCL2 in the CNS was identified in infected astrocytes [54], as also observed upon in vitro infection of these cells with HIV-1 [55]. Increased levels of CCL2, but not of other chemokines, in the CNS have been linked to the enhanced transmigration of leukocytes across the BBB [56].…”

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Microglia and astrocytes maintain homeostasis within the CNS during health; however, they also mediate very specific disease mechanisms as illustrated in Alexander's disease in which GFAP polymorphisms result in demyelination, neurodegeneration, and delayed development (56,57) or HIV-associated encephalopathy during which microglia/macrophages and astrocytes are infected by HIV-1, resulting in neuroinflammation with axonal loss (58,59). Hence it is plausible that a retroviral env-encoded glycoprotein such as Syncytin-1 might induce ER stress and inflammation in glia, which results in impaired myelin homeostasis and limited remyelination postinjury.…”

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

“…This highlights the importance of the delicate balance between immunocompetence versus over-activation of microglia in maintaining neuronal health. Compared to HIV-infected microglia and perivascular macrophages that are active in HIV viral replication and inflammatory molecule production, astrocytes are thought to play a greater role in chemotaxis and activation of monocytes/macrophages rather than in active viral replication (Muratori et al, 2010). There also appears to be a CXCR4-mediated microglia-astrocyte signaling cascade, leading to the release of the neurotoxin glutamate (Bezzi et al, 2001).…”