Proinflammatory cytokines and HIV‐1 synergistically enhance CXCL10 expression in human astrocytes

Abstract

HIV encephalitis (HIVE), the pathologic correlate of HIV-associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HAD/HIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV-infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon-γ inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the pro-inflammatory cytokines, IFN-γ and TNF-α, are also markedly increased in CNS tissues during HIV-1 infection. In the present study we hypothesized that the interplay of host cytokines and HIV-1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV-1 and the proinflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/2, AKT, and p38), and NF-κB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV-1 and cytokine mediated up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.

The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice

“…Activation of p38 MAPK is instrumental in inflammatory signaling in glia, including induction of CXCL10 (Williams et al, 2009). β-FNA inhibited IL-1β-induced p38 MAPK activation in NHA (Fig.…”

Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells

“…43 Interestingly, p38 MAPK has also been implicated in the production and release of IP10 in astrocytes exposed to HIV-1 and Tat. [44][45][46] In addition, HIV-1 and Tat were reported to activate p38 MAPK in infected or stimulated neurotoxic monocytes and MDM. 47 Furthermore, p38 MAPK activation in iDC appears to be critical to the role played by these cells in the differentiation of Th17 helper T cells, which are preferentially targeted by HIV and ultimately are severely depleted, especially in the intestine.…”

Brucella abortus Induces the Secretion of Proinflammatory Mediators from Glial Cells Leading to Astrocyte Apoptosis

“…Although these proinflammatory mediators could hypothetically play a role either directly or indirectly in host defense against B. abortus, they may also play an important role in the initiation, propagation, and regulation of inflammatory innate immune responses in the brain. Proinflammatory mediators including IL-1␤, IL-6, TNF-␣, nitric oxide, reactive oxygen species, and chemokines released by astrocytes and microglia were shown to act contributing to diseases like HIV-encephalitis, [43][44][45] Toxoplasma encephalitis, Alzheimer disease, 43,45 and multiple sclerosis, 45 among others. In fact, the presence of a neutrophil infiltrate in the brain of mice injected with HKBA could reflect the ability of astrocytes and microglia to secrete KCone the major chemoattractants responsible for recruiting neutrophils in mice 46 -on infection/stimulation with B. abortus.…”