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Wenxin Ma, Sean Silverman, Lian Zhao, Rafael Villasmil, Robert N Fariss, Maria M Campos, Juan Amaral, Wai T Wong; Genetic ablation of TGFbR2 in microglia results in neuroinflammatory and neurodegenerative changes in the retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2530. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Microglia are resident immune cells that play important roles in maintaining tissue homeostasis in the healthy retina. Inappropriate microglial activation in retinal disease has been shown to drive inflammation-mediated neurodegeneration. We explore the role of direct TGFβ signaling to retinal microglia in maintaining a “resting” physiological state and preventing inappropriate activation.
A transgenic CX3CR1CreER/+;TGFbR2flox/flox mouse model was used to inhibit direct TGFβ signaling to microglia by genetic ablation of TGFbR2 in adult mice in an inducible and specific manner. The 2 and 8 weeks mice following administration of Tamoxifen were analyzed with in vivo fundus imaging and ERG testing, histological analysis, and mRNA expression profiling.
Two weeks following TGFbR2 ablation, microglia in the IPL and OPL demonstrated increased density, decreased ramification, and altered positioning, adhering closely to retinal vessels. Immunohistochemical analyses showed increased microglial expression of activation (MHC2(IA/IE), CD68 and CD74) and proliferation (Ki67) markers. ERG evaluation demonstrated decrements in light-adapted b-wave amplitudes at 2 weeks and decrements in both light- and dark-adapted b-wave amplitudes at 8 weeks post-ablation, with relative sparing of a-wave amplitudes. Analysis of retina structure on OCT and histology showed decreased retinal thickness, due primarily to thinning in the IPL, OPL and ONL layers. Increased Müller cell gliosis was evident from increased GFAP immunopositivity. mRNA expression profiling of TGFbR2-ablated retinas and flow-sorted retinal microglia showed upregulation in microglial activation markers (MHC2, CD68, CD74), chemokines (CCL2, CCL8), complement factors (C3, C4b), and markers of gliosis (GFAP), and downregulation in markers of resting microglia (Cx3cr1, Tmem119, P2ry12, Siglec-H) and neurotrophic factors (BDNF, IGF1 and PDGF-A).
Direct TGFβ signaling to microglia is required to maintain normal retinal microglia cell morphology, distribution, and activation state. The loss of “resting” microglial physiology resulted in increased gliosis, neuronal cell loss, and synaptic dysfunction, underscoring endogenous functions of microglia. Perturbations in TGFβ signaling may confer increased vulnerability to neuroinflammatory and neurodegenerative retinal pathologies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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