Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia

Abstract

Human immunodeficiency type-1 (HIV-1) infection is known to cause disorders of the CNS, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNF-alpha) released by infected microglia and macrophages play a role in neuronal injury seen in HAD patients. Accordingly, studies suggest that the level of TNF-alpha mRNA increases with increasing severity of dementia in patients, and that inhibitors of TNF-alpha release reduces neuronal injury in murine model of HAD. However, the exact role of TNF-alpha in relation to neuronal dysfunction is a matter of ongoing debate. One school of thought hails TNF-alpha as the inducer and mediator of neurodegeneration and their evidence suggest that TNF-alpha kill neurons directly by recruiting caspases or may kill indirectly by various means. In sharp contrast to this, another concept theory envisages a role for TNF-alpha in negotiating neuroprotection during HAD. The current compilation examines these contradictory concepts, and evaluates their efficacy in the light of TNF-alpha signaling. It also attempts to elaborate the current consensus outlook of TNF-alpha's role during HAD.

Fig. 1. Comparative display of potential modulation of cell death or protection by TNF-α during HAD

The microenvironment of a neuron during HAD is represented by viral entry and subsequent activation of glial cells. Viral toxins can directly induce neuronal death or may trigger gliosis, which ultimately leads to neuronal damage. TNF-α is significantly present in this environment although its exact role is debatable. (a) Represents possible roles of TNF-α as an inducer of neurotoxicity and degeneration. It may directly kill neurons through its receptors to activate caspases, or may synergistically enhance toxicity of viral toxins like gp120. Indirect modes of killing include NO-mediated peroxynitrite toxicity, and up-regulation of gene products, which are either directly neurotoxic (α-chemokines) or may indirectly induce neuronal injury (e.g. up-regulation of ICAM and VCAM aid in HIV-1 trafficking across BBB). Moreover, it induces the production of excitotoxins from glial cells, like glutamate and l-cysteine, thus offering the neuron a lethal excitotoxic environment. (b) represents possible roles of TNF-α as a neuroprotector. TNF-α acts via NF-κB to up-regulate several pro-survival gene products. Pre-treatment with TNF-α leads to Ca²⁺ and K⁺ homeostasis. In addition, TNF-α induces the production of neuroprotective β- and δ- chemokines. These chemokines significantly attenuate toxicity mediated by viral proteins like gp120. Moreover, β-chemokines may protect neurons by interacting with their receptors.

Fig. 1. Comparative display of potential modulation of cell death or protection by TNF-α during HAD

The microenvironment of a neuron during HAD is represented by viral entry and subsequent activation of glial cells. Viral toxins can directly induce neuronal death or may trigger gliosis, which ultimately leads to neuronal damage. TNF-α is significantly present in this environment although its exact role is debatable. (a) Represents possible roles of TNF-α as an inducer of neurotoxicity and degeneration. It may directly kill neurons through its receptors to activate caspases, or may synergistically enhance toxicity of viral toxins like gp120. Indirect modes of killing include NO-mediated peroxynitrite toxicity, and up-regulation of gene products, which are either directly neurotoxic (α-chemokines) or may indirectly induce neuronal injury (e.g. up-regulation of ICAM and VCAM aid in HIV-1 trafficking across BBB). Moreover, it induces the production of excitotoxins from glial cells, like glutamate and l-cysteine, thus offering the neuron a lethal excitotoxic environment. (b) represents possible roles of TNF-α as a neuroprotector. TNF-α acts via NF-κB to up-regulate several pro-survival gene products. Pre-treatment with TNF-α leads to Ca²⁺ and K⁺ homeostasis. In addition, TNF-α induces the production of neuroprotective β- and δ- chemokines. These chemokines significantly attenuate toxicity mediated by viral proteins like gp120. Moreover, β-chemokines may protect neurons by interacting with their receptors.

Fig. 2. Pathways originating from TNF-R1 and TNF-R2 leading to cell survival or death

While the membrane-bound form of TNF-α can bind to both receptors with similar affinity, the soluble form binds TNF-R2 with lesser affinity. Binding of the trimeric cytokine ligand leads to receptor trimerization. This triggers intracellular signal transduction, although activated TNF-R2 may be cleaved by metalloproteinases to be released as TNF-bound-soluble receptor. Once activated, both receptors recruit adaptor molecules. TNF-R1 binds to TRADD through its death domain and recruits FADD or RIP. Binding of FADD deploys the caspase train leading to apoptosis via mitochondria-dependent and independent pathways. Alternately, RIP recruits TRAF2 to the receptor complex. TRAF2 activates the upstream kinases of different MAP kinase pathways that may lead to inflammation and cell death via AP-1-activated genes. On the contrary, TRAF2 can induce survival signal by activating IKK by binding to its NEMO subunit. It may also activate IKK via other upstream molecules like RIP1 and NIK. Activated IKK phosphorylates IκB, setting it up for ubiquitination-dependent degradation, which then releases p65–p50 heterodimer of NF-κB to translocate into the nucleus and primarily activate survival genes. NF-κB may also induce inflammatory genes, which could then tilt the balance towards apopto-sis. TNF-R2 also utilizes the same pathway for up-regulating survival gene products via NF-κB. However, it is also postulated to induce death via FADD-dependent caspase activation.