Table 2.
Comparison of studies using PLX5622 to deplete microglia in various models of viral encephalitis (part 2)
| Study | Sanchez et al. [274] | Funk et al. [107] | Wheeler et al. [344] | Waltl et al. [334] | Seitz et al. [279] | Fekete et al. [96] | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Virus | Daniel’s strain of TMEV | WNV-NY, strain 3000.0259 | Attenuated WNV-NS5- E218A | Neuro-attenuated variant of the JHMV strain of MHV | N1347A, an rJ macrodomain point mutant virus | Recombinant parental JHMV (rJHMV) |
Daniel’s strain of TMEV | WNV-NY99 | p3 strain of JEV | PRV-Bartha derivative, PRV-Bartha-Dup-Green (BDG) |
| Enhanced neuroinflammation/ neurodegeneration? | Axonal damage and demyelination in spinal cords | N/R |
Increased neuronal apoptosis in the hippocampus and cerebellum at dpi 6. |
N/R | Increased: neuroinflammation, perivascular infiltrates, astrogliosis and neurodegeneration. | N/R | N/R | |||
| Change in macrophage infiltrate in PLX5622-treated animals? | N/R | N/R |
Decreased numbers of macrophages Reduced CD86 expression. |
Increased numbers of macrophages. Reduced expression of MHC-II, increased expression of Ly6C and differential expression of 235 genes. |
N/R | No change | N/R | Decreased numbers of macrophages. | ||
| Change in cytokine production in the CNS of PLX562- treated animals? | N/R | N/R |
Decreased RNA: IFN-β, IFN-γ, TNF, NOS2, CD86 & CD68 (brain). |
Increased RNA: IFN-β, IL6 at dpi 3 and IFN-α, IFN-β, IL6 at dpi 5. No change in protein: IFN-α, IFN-β & IL6 at dpi 5 (brain). |
N/R |
Decreased RNA: TGF-β1 (brain). Increased RNA: IL-6 (brain), IL10 (brain) & IFN-γ (brain & spinal cord). |
Increased RNA: CCL2 at dpi 6 and CCL2, CCL7, CXCL9 & CXCL10 at dpi 9 (brain). | Increased RNA: CCL3 at dpi 8 (brain). | Decreased protein: IL-1α & RANTES (hypothalamic brain tissue). | |
| Altered T cell response in the CNS in PLX5622-treated animals? | N/R | N/R |
Increased percentage and number of CD8+ T cells. CD8+CD45+NS4B+ T cells showed a decreased frequency of CD69+ and CD160+ cells and reduced expression of CD69 and CD160. All relative to infected, non-microglia-depleted animals. |
Decreased percentage & numbers of CD4+ T cells & virus-specific CD4+ T cells. Decreased percentage & numbers T regs. All relative to infected, non-microglia-depleted animals. |
N/R |
Increased T regs in the spinal cord and hippocampus (relative to microglia-depleted, non-infected animals). Decreased numbers CD4+ and CD4+CD44+ T cells in the whole brain (relative to non-depleted, infected animals). |
N/R |
No change in the number of CD8+CD3+ T cells in the brain (relative to non-depleted and/or infected animals). |
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| Systemic responses in PLX5622-treated animals | N/R |
Loss of CD80 (percentage & numbers) & CD86 (percentage & mean fluorescence intensity) expression on MHC-II+CD11c+CD45+ (DCs) cells, increase in the numbers of CD4+ and CD8+ T cells, no change in CD69+ on CD8+ CD45+ T cells and no change in WNV-specific NS4B+ tetramer staining of CD8+CD45+ cells in the spleen of WNV-NS5- E218A infected, PLX5622-treated animals Decreased CD80 expression on DCs in the blood and decreased CD86 on DCs pDLN at dpi 4 (WNV-NY, f.p.) Reduced numbers of CD45+MHC-II+CD11c+ and CD11b-CD11c+ in the blood in non-infected, PLX-treated animals No change in antigen-presenting cell (APC) populations in the spleen or BM in non-infected, PLX5622-treated animals No changes in T cells, CD11b+, Ly6C+ or Ly6G+ cells in spleen, BM or blood in non-infected, PLX5622-treated animals |
No change in the number of CD11b+ cells in the non-infected spleen No change in the total number of cells on dpi 3 or 5 in the draining cervical lymph nodes (dCLN) in i.c. MHV-infection PLX5622 treatment did not change the number of virus-specific CD4+ or CD8+ T cells after i.p. infection with rJ |
Reduced number of CSF1R monocytes in the blood in PLX5622-treated mock and infected groups compared to non-PLX-treated animals No change CD4+ and CD8+ ratio in the spleen of PLX5622-treated animals No change in the number Iba1+ macrophages in the spleen (by immunohistochemistry) |
N/R |
PLX5622 did not cause a significant reduction in circulating or splenic myeloid populations: monocytes, granulocytes, macrophages and B cells Increase in circulating granulocytes (non-significant – infected depleted vs infected non-depleted, significant – infected depleted vs non-infected depleted) Decrease in circulating CD8+ T cells (non-significant – infected depleted vs infected non-depleted, significant – infected depleted vs non-infected depleted) |
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| Protective role of microglia | Microglia mediate antiviral responses in the CNS |
Microglia are important in the restimulation of a CD8+ T cell in the CNS for an effective antiviral T cell response to control viral spread Lack of virologic control was specifically due to the reduction in APCs (as measured by macrophage and microglial expression of B7 molecules) in the CNS, important for a CD8+ T cell response |
Microglia are important in the earliest stages of disease, preventing the neurological spread of the virus by restimulating CD4+ T cells that enter the brain The absence of microglia was associated with the infiltration of immature macrophages and the reduction in MHC-II in the CNS (on microglia and macrophages), preventing the local reactivation of CD4+ T cells for an effective antiviral T cell response |
Microglia depletion resulted in increased numbers of T regs and IL-10, suppressing cytotoxic CD8+ T cell activity and preventing an effective antiviral T cell response to control viral spread | Microglia mediate antiviral responses in the CNS | The protective role of microglia relies on the rapid and precise migration of microglia to virally infected neurons and the subsequent phagocytosis to prevent viral spread and the presence of viral antigens in the brain | ||||