LXR activation prevents development of diabetic retinopathy (DR) in db/db mice by controlling cholesterol and stem cell profiles

Abstract

Purpose : Diabetic dyslipidemia, common in type 1 and type 2 diabetes, contributes to the pathogenesis of DR. LXR activation enhances cholesterol removal via reverse cholesterol transport (RCT) and reduces inflammatory gene expression, regulating immune responses and development of inflammation. Systemic inflammation in diabetes is mediated by myeloidosis in the bone marrow(BM) which contributes to the pathogenesis of DR. We examined the effect of DMHCA, an LXR agonist on DR and on changes in the BM.

Methods : db/db mice were fed DMHCA (8mg/kg body weight/day for 6 months) containing chow or normal chow from diabetes onset. Mice were euthanized and retinal tissue and BM cells were collected. Retinal inflammation was assessed by quantitation of monocytes, M1 and M2 macrophages, CD45⁺ cells and CCL-2 expression by flow cytometry; and retinal lipids, by Mass Spectroscopy. Acellular capillaries and electroretinograms(ERG) were performed. The BM supernatant was analyzed for cytokines and BM progenitor cells were determined by flow cytometry and colony-forming units.

Results : DMHCA-treated db/db (mice showed a reduction in classical (proinflammatory) monocytes (2.2±1 p=0.03) in compared to db/db (20±2), while the nonclassical (anti-inflammatory) monocytes increased in DMHCA–treated db/db (97±2 p=0.03) compared to db/db (80±3). CCL-2 expression was reduced in DMHCA-treated db/db mice (0.9±0.1 p=0.02) compared to db/db mice (1.7±0.2). Retinal CD45⁺ cells were increased in db/db mice (55±7 p=0.05) and reduced in DMHCA-treated db/db mice (31±7). Less cholesterol was found in retinas of DMHCA db/db mice. There was a significant improvement in the ERG scotopic response 229±50 in DMHCA db/db compared to db/db 76±20µV. Interestingly, DMHCA decreased the percentage of granulocyte macrophage progenitors (1.9±0.3 vs 2.8±0.6 db/db p=0.01) and TNFα (60±20 vs 170±30 db/db p=0.03) and IL-3 (0.26±0.03 vs 0.6±0.03 db/db p=0.01) levels in BM supernatant.

Conclusions : The favorable effects of LXR activation by DMHCA on the diabetic retina include improved visual response and reduced infiltration of proinflammatory cells into the retina. These beneficial effects are mediated largely by DMHCA dramatic impact on BM function leading to reduced systemic inflammation.

This is a 2020 ARVO Annual Meeting abstract.