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

Abstract

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.

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

“…Sections were stained with hematoxylin and eosin, as previously described. 2,15 Histopathological Analysis of DRG Morphology…”

“…2,15 Overall pathology was scored via the following criteria: i) mild: scattered infiltrating mononuclear cells with rare evidence of neuronophagia and/or neuronal loss; ii) moderate: increased numbers of infiltrating mononuclear cells with occasional neuronophagia and/or neuronal loss; and iii) severe: abundant infiltrating mononuclear cells, frequent neuronophagia, and neuronal loss were all present. 2,15,16 Immunohistochemistry DRG sections were stained with either anti-SIV protein p28 (Fitzgerald, Acton, MA), the pan-macrophage marker anti-CD68 (clone KP1; Dako, Carpinteria, CA), the scavenger receptor anti-CD163 (clone MCA1853; Serotec, Raleigh, NC), the early inflammatory marker anti-MAC387 (clone M0747; Dako), anti-BrdU (clone M0744; Dako), the T-lymphocyte marker anti-CD3 (clone A0452; Dako), or antievascular cell adhesion molecule (VCAM)-1 (4E8 clone; Antibodies-Online, Atlanta, GA), as previously described. 2,16 Immunohistochemistry Quantitation in DRGs…”

“…2,15,16 Immunohistochemistry DRG sections were stained with either anti-SIV protein p28 (Fitzgerald, Acton, MA), the pan-macrophage marker anti-CD68 (clone KP1; Dako, Carpinteria, CA), the scavenger receptor anti-CD163 (clone MCA1853; Serotec, Raleigh, NC), the early inflammatory marker anti-MAC387 (clone M0747; Dako), anti-BrdU (clone M0744; Dako), the T-lymphocyte marker anti-CD3 (clone A0452; Dako), or antievascular cell adhesion molecule (VCAM)-1 (4E8 clone; Antibodies-Online, Atlanta, GA), as previously described. 2,16 Immunohistochemistry Quantitation in DRGs…”

“…2 The number of BrdU þ monocytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macrophages play a significant role in DRG pathogenesis. …”

“…1 Using a CD8-depleted SIV-infected rhesus macaque model of peripheral neuropathy, we have shown that accumulation of recruited [bromodeoxyuridine (BrdU) þ MAC387 þ ] monocytes/macrophages was associated with severe DRG pathology. 2 The number of BrdU þ monocytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macrophages play a significant role in DRG pathogenesis.…”