Abstract
Purpose :
The expansion of microglial population is a hallmark of retinal degeneration, which contributes to disease progression. However, the origin of the cells involved is still controversial and whether microglial cells are locally renewed or recruited from the bloodstream is unclear. The aim of this study was to determine the relative contribution of microglial proliferation and infiltration and to identify the factors that regulate microglial expansion, using the rd10 mouse model of retinitis pigmentosa.
Methods :
Microglia proliferation is dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling. Quantitative RT-PCR and ELISA were used to assess the expressions of CSF1R and its two ligands (CSF1 and IL-34) in the rd10 retina at different ages (P16, P19, P22). Recombinant murine CSF1 or murine IL-34 was injected to the eyes to study their role in regulating microglial proliferation. PLX5622, a selective inhibitor of the CSF1R tyrosine kinase activity, was administered (50mg/kg) to block microglial proliferation. Immunohistochemistry was used to evaluate microglia proliferation and photoreceptor cell morphology and density in rd10 mouse retinas. Apoptotic photoreceptor death was also assessed by TUNEL assay.
Results :
Increased proliferating microglial cells (BrdU+) was observed in P19 and P22 rd10 mouse retinas. Additionally, CSF1R, CSF1 and IL-34 expressions were upregulated in the rd10 retinae at P19 and P22. We found a significantly higher number of proliferating microglial cells (BrdU+) in the rd10 mice administered with CSF1 or IL-34 compared with saline control. The administration of PLX5622 caused a significant reduction in microglial proliferation (BrdU+), and slowed photoreceptor damage and disease progression.
Conclusions :
Our results demonstrate that resident microglial proliferation contributes to the expansion of microglial population during RP progression. Our data also support the important role of signaling through CSF1R by CSF1 or IL-34 as the major driver of microglial proliferation during the course of the disease. These results suggest that regulation of the CSF1R signalling pathway may delay the progression of photoreceptor degeneration.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.