Neuroinflammation in HIV-Related Neuropathic Pain

Abstract

In the management of human immunodeficiency virus (HIV) infection around the world, chronic complications are becoming a new problem along with the prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those with a low viral load undergoing long-term treatment with antiviral drugs, negatively influencing the adherence to disease management and quality of life. A large proportion of chronic pain is neuropathic pain, which defined as chronic pain caused by nervous system lesions or diseases, presenting a series of nervous system symptoms including both positive and negative signs. Injury caused by HIV protein, central and peripheral sensitization, and side effects of antiretroviral therapy lead to neuroinflammation, which is regarded as a maladaptive mechanism originally serving to promote regeneration and healing, constituting the main mechanism of HIV-related neuropathic pain. Gp120, as HIV envelope protein, has been found to be the major toxin that induces neuropathic pain. Particularly, the microglia, releasing numerous pro-inflammatory substances (such as TNFα, IL-1β, and IL-6), not only sensitize the neurons but also are the center part of the crosstalk bridging the astrocytes and oligodendrocytes together forming the central sensitization during HIV infection, which is not discussed detailly in recent reviews. In the meantime, some NRTIs and PIs exacerbate the neuroinflammation response. In this review, we highlight the importance of clarifying the mechanism of HIV-related neuropathic pain, and discuss about the limitation of the related studies as future research directions.

Keywords: Chemokine; HIV; Human immunodeficiency virus; microglia; neuroinfalmmation; neuropathic pain (NP).

FIGURE 1

Gp120 binds to the CXCR4 receptor, and then triggers a series of downstream cellular signaling events involving TNFα/CREB/NMDAR, Wnt/β-catenin/FKN, Wnt5a/JNK/CAMKII and PLC/PKC/caspase 3 signal pathway. The interaction between neurons and microglia in response to infection induces neuropathic pain via different mechanisms. A. Stimulated by gp120, microglia up-regulate TNFα in a way of paracrine, TNFα/TNFR1 signal results in the accumulation of reactive oxygen species in mitochondria, which induced the phosphorylation of CREB triggering the pC/EBP (Zhang et al., 2004). C/EBP promotes recycling of NMDAR regulating the concentration of Ca2+ intracellularly (Wang et al., 2013; Hansen et al., 2018). B. FKN specifically expressed in neurons is upregulated by gp120, which activates microglia through CX3CR1. C. Transcription of Wnt5a is increased after gp120 application, stimulate the production of inflammatory cytokines in a paracrine fashion. Wnt5a/JNK is critical for TNFα expression, whereas Wnt5a/CaMKII is necessary for IL-1β and P2X7R is another factor predominant in driving IL-1β release. The expression of IL-6 is co-regulated by both pathways. D. Exposure of neurons to gp120 produces transient outward K+ currents in a PKC-dependent manner. The alteration of intracellular K+ homeostasis leads to neuronal apoptosis by activation of caspase-3. PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; Casp 3, caspase 3; Fzd2, Frizzled family receptor 2; Ror2, receptor tyrosine kinase-like orphan receptor 2.

FIGURE 2

Schematic diagram for the interaction between microglia, astrocytes and oligodendrocytes in neuroinflammation. Stimulated by pathogen or injury, the production of cytokines, chemokines, and growth factors by microglia may induce activation on astrocytes and oligodendrocyte, which accelerates the neuroinflammation in CNS, leading to central sensitization. Conversely, there are some factors (e.g., TGF-β, IL-10) that attenuate the development of neuroinflammation, serving the function of neuroprotection. TGF-β: transforming growth factor-β; INFγ: interferon γ.