Possible involvement of macrophages in the pathogenesis of HIV-induced distal sensory neuropathic pain

[Speaker] Mpumelelo Ntogwa:1
[Co-author] Satoshi Imai:1, Ren Hiraiwa:1, Madoka Koyanagi:1, Takayuki Nakagawa:1, Kazuo Matsubara:1
1:Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan

BACKGROUND: Distal sensory neuropathy (DSN) is a hallmark of human immunodeficiency virus (HIV) infections, affecting as many as 50% of all individuals infected with HIV, and can result in persistent and disabling pain. Direct neurotoxicity through infection of neurons with HIV has been proposed to be associated with the pathogenesis of HIV DSN. However, it remains controversial whether HIV can enter neurons and thus be directly neurotoxic. Alternatively, a growing body of evidence suggests that the indirect neurotoxicity of HIV through inflammatory responses to viral envelope proteins, such as gp120, is an essential mechanism of HIV DSN pathogenesis. In this study, we examined the impact of gp120 on innate immune systems that could explain how the envelope protein induces DSN.
METHODS: The HIV DSN model was generated by applying either HIV-gp120 (IIIB and MN strain) or its vehicle to the sciatic nerve of C57BL/6J mice (5-7 weeks old), using oxidized cellulose to deliver proteins directly to the sciatic nerve. Paw withdrawal thresholds to a tactile stimulus to the ipsilateral hindpaw was assessed at baseline and on post-surgical days 3, 7, 14, 21 and 28. Spontaneous pain-associated behaviors were assessed by visual observation of the operated limb on post-surgical day 7. Animals were sacrificed and perfused on day 7 to collect samples of the sciatic nerve, dorsal root ganglion and spinal cord for immunohistochemistry and flow cytometry examination.
RESULTS: Application of gp120 IIIB or MN strain to the sciatic nerve significantly reduced paw withdrawal threshold to a tactile stimulus in the ipsilateral hind paw 7 days after treatment. Spontaneous pain-like behaviors were also significantly increased 7days after gp120 treatment. Flow cytometry and immunohistochemical studies revealed a marked increase in F4/80- and Iba1-positive macrophage within the ipsilateral sides of both gp120 treated sciatic nerves and DRG 7days after gp120 treatment. Peripheral macrophage deletion by clodronate liposomes completely abolished both gp120-induced mechanical allodynia and spontaneous pain-like behaviors.
CONCLUSIONS: Present findings suggest that macrophages play a key role in the HIV pathogenesis of evoked and spontaneous pain in HIV DSN. Further identification of key molecules released by macrophages which mediate HIV DSN is needed.

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