Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

Abstract

Aim: We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression.Methods: Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats.Results: Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure.Conclusions: Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.

Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4

“…23 We speculate that APOE may be similarly upregulated in microglia in glaucoma, as microglial reactivity has been found to contribute to glaucoma pathogenesis. [26][27][28][29][30] Another interesting parallel can be made between our findings and the association of APOE with AMD, where APOE ε4 has also been found to be inversely associated with disease. [49][50][51][52] The reason why the same APOE allele has an opposing relationship in ocular neurodegenerative diseases and AD is presently poorly understood.…”

“…[23][24][25] Furthermore, TREM2 and APOE have been identified as key regulators of the microglial molecular phenotype associated with neurodegeneration (the so-called microglial neurodegenerative or disease-associated microglia molecular signature). [23][24][25] Given that microglia have also been implicated in the pathogenesis of glaucoma [26][27][28][29][30] and that APOE is upregulated in the retina and the aqueous humor of patients with glaucoma, 31,32 we hypothesized that APOE and TREM2 may have genetic associations with POAG as well.…”

Frataxin overexpression in Müller cells protects retinal ganglion cells in a mouse model of ischemia/reperfusion injury in vivo

“…in experimental glaucoma 64 – 66 . Our results are in agreement with studies showing that the expression of MHCII is upregulated in activated microglia during axonal degeneration induced by ocular hypertension in rats 67 , 68 and downregulated MHCII is associated with less severe axonal degeneration in a model of glaucoma by chronic increased IOP 68 . Reduced expression levels of MHCII may inhibit the activation of invading T-cell, thereby diminishing the inflammatory cascade leading to tissue damage 69 , 70 .…”

Gradual Increase in Environmental Light Intensity Induces Oxidative Stress and Inflammation and Accelerates Retinal Neurodegeneration

“…Then, retinal cell suspensions were filtered, to prevent clumps, using a 30-µm strainer (BD Biosciences, San Diego, CA, USA), and labeled with a cocktail of five antibodies acquired from e-Bioscience (San Diego, CA, USA): anti-CD11b-PE (clone M/170), anti-CD45-FITC (clone 30-F11), anti-CD11c-PerCpCy5.5 (clone N418), anti-major histocompatibility complex (MHC) class II (I-A/I-E)-PECy7 (clone M5/114.15.2), and anti-CD169-eFluor 660 (clone SER-4). After discarding doublets and debris events, the CD11b-positive cells (a marker of myeloid cells, as microglia and infiltrating macrophages) 36 – 38 were analyzed for their immunoreactivity against MHC class II (activated cells), 39 – 41 CD11c (a marker of dendritic and microglia cell populations), 42 – 44 and sialoadhesin (CD169, which stains activated macrophages and microglial cell populations). 45 , 46 Immunoreactivity against CD169, CD11c, and MHC class II antibodies in CD11b-positive cells allowed analysis of subpopulations of cells that contribute to the inflammatory process, as do the activated microglia and infiltrating cells.…”