Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

Laast, Victoria A.; Shim, Beom; Johanek, Lisa M.; Dorsey, Jamie L.; Hauer, Peter; Tarwater, Patrick M.; Adams, Robert J.; Pardo, Carlos A.; McArthur, Justin C.; Ringkamp, Matthias; Mankowski, Joseph L.

doi:10.1016/j.ajpath.2011.07.047

Cited by 51 publications

(72 citation statements)

References 44 publications

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“…21 Previous studies of SIV-PN examined CD68 þ or Iba-1 macrophages in the DRG. 17,18,20 Herein, CD68 was used as a marker for resident macrophages, and CD163 þ cells represented M2-like perivascular macrophages. CD163 is a scavenger receptor expressed on activated mononuclear cells and is shed in its soluble form.…”

Section: Discussionmentioning

confidence: 99%

“…Because the epidermis can be densely innervated in macaque skin compared with human, manual counting is difficult. 17,35,36 To address this, the samples in this study were quantified using an unbiased stereology protocol that has been developed at the Johns Hopkins (Baltimore, MD) Cutaneous Nerve Laboratory. 17,35,36 This approach requires that a technician define the boundaries of the structure that is counted.…”

Section: Skin Punch and Ienfd Measurementmentioning

confidence: 99%

“…Previous studies have used CD68 or ionized calcium binding adaptor protein 1 (Iba-1) as monocyte/macrophage markers in the DRG. 17,20,24 However, these markers do not differentiate between circulating and infiltrating monocytes/macrophages and resident macrophages. It is likely that resident macrophages (CD68 þ and CD163 þ ) and infiltrating macrophages (MAC387 þ ) play different roles during HIV-associated DRG damage, 25 as do M1 versus M2 cells at the DRG.…”

mentioning

confidence: 97%

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Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy

Lakritz

Bodair

Shah

et al. 2015

The American Journal of Pathology

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HIV-associated sensory neuropathy remains the most common neurological complication of HIV infection and is characterized by dorsal root ganglion (DRG) inflammation and intraepidermal nerve fiber density (IENFD) loss. Chronic peripheral immune cell activation and accumulation may cause damage to the DRG, but has not been fully investigated yet. By using an SIV-infected, CD8-lymphocyte-depleted rhesus macaque model, we defined immune cells surrounding DRG neurons and their role in DRG pathology, measured cell traffic from the bone marrow to the DRGs using 5-bromo-2-deoxyuridine (BrdU) pulse, and serially measured IENFD. We found an increase in CD68(+) and CD163(+) macrophages in DRGs of SIV-infected animals. MAC387(+) recently recruited monocytes/macrophages were increased, along with BrdU(+) cells, in the DRGs of SIV-infected macaques. We demonstrated that 78.1% of all BrdU(+) cells in DRGs were also MAC387(+). The number of BrdU(+) monocytes correlated with severe DRG histopathology, which included neuronophagia, neuronal loss, and Nageotte nodules. These data demonstrate that newly recruited MAC387(+)BrdU(+) macrophages may play a significant role in DRG pathogenesis. IENFD decreased early (day 21), consistent with the development of sensory neuropathy in SIV-infected macaques. Decreased IENFD was associated with elevated BrdU(+) cells in the DRG. These data suggest that increased recruitment of macrophages to DRG is associated with severe DRG histopathology and IENFD loss.

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Section: Discussionmentioning

confidence: 99%

Section: Skin Punch and Ienfd Measurementmentioning

confidence: 99%

mentioning

confidence: 97%

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Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy

Lakritz

Bodair

Shah

et al. 2015

The American Journal of Pathology

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“…These include neonatal cats infected with the feline immunodeficiency virus [113] and macaques infected with a neurovirulent strain of simian immunodeficiency virus [114]. The macaque model has been useful to demonstrate that the simian immunodeficiency virus-infected animals have defective regenerative capacity of their peripheral nerves [115], and the distal axonal degeneration (as evidenced by reduced intraepidermal nerve fiber densities) seen in these macaques is associated with mitochondrial dysfunction and increased oxidative stress in the distal nerves, but not in the proximal nerves [116].…”

Section: Human Immunodeficiency Virus-associated Sensory Neuropathymentioning

confidence: 99%

Animal Models of Peripheral Neuropathies

Höke

2012

Neurotherapeutics

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Peripheral neuropathies are common neurological diseases, and various animal models have been developed to study disease pathogenesis and test potential therapeutic drugs. Three commonly studied disease models with huge public health impact are diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, and human immunodeficiency virus-associated sensory neuropathies. A common theme in these animal models is the comprehensive use of pathological, electrophysiological, and behavioral outcome measures that mimic the human disease.

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“…Previous research suggests that monocyte/macrophages traffic to the dorsal root ganglia (DRG) and inflict damage during HIV and SIV infection [42,[44][45][46]. These studies used CD68 + or Iba-1 to characterize resident macrophages in the DRG [42,46,47].…”

Section: Monocyte Traffic and Activation In Drg During Siv Peripheralmentioning

confidence: 99%

Macrophage Polarization in AIDS: Dynamic Interface between Anti-Viral and Anti-Inflammatory Macrophages during Acute and Chronic Infection

Burdo

Walker

Williams

2015

J Clin Cell Immunol

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Monocyte and macrophage inflammation in parenchymal tissues during acute and chronic HIV and SIV infection plays a role in early anti-viral immune responses and later in restorative responses. Macrophage polarization is observed in such responses in the central nervous system (CNS) and the heart and cardiac vessels that suggest early responses are M1 type antiviral responses, and later responses favor M2 restorative responses. Macrophage polarization is unique to different tissues and is likely dictated as much by the local microenvironment as well as other inflammatory cells involved in the viral responses. Such polarization is found in HIV infected humans, and the SIV infected animal model of AIDS, and occurs even with effective anti-retroviral therapy. Therapies that directly target macrophage polarization in HIV infection have recently been implemented, as have therapies to directly block traffic and accumulation of macrophages in tissues.

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Macrophage-Mediated Dorsal Root Ganglion Damage Precedes Altered Nerve Conduction in SIV-Infected Macaques

Cited by 51 publications

References 44 publications

Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy

Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy

Animal Models of Peripheral Neuropathies

Macrophage Polarization in AIDS: Dynamic Interface between Anti-Viral and Anti-Inflammatory Macrophages during Acute and Chronic Infection

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