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Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection.

ABSTRACT: HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B₄ isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4⁺ and tropomyosin receptor kinase A-positive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4⁺ nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.

SUBMITTER: Robinson JA

PROVIDER: S-EPMC7322364 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1 beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1 beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.

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Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection.

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