Toll-like receptor 4 in bone marrow-derived cells contributes to the progression of diabetic retinopathy.

Hui Wang,Guoliang Wang,Haojun Shi,Jing Zhang,Jinxiang Zhang,Fagang Jiang,Qing Xiao

doi:10.1155/2014/858763

Abstract

Diabetic retinopathy (DR) is a major microvascular complication in diabetics, and its mechanism is not fully understood. Toll-like receptor 4 (TLR4) plays a pivotal role in the maintenance of the inflammatory state during DR, and the deletion of TLR4 eventually alleviates the diabetic inflammatory state. To further elucidate the mechanism of DR, we used bone marrow transplantation to establish reciprocal chimeric animals of TLR4 mutant mice and TLR4 WT mice combined with diabetes mellitus (DM) induction by streptozotocin (STZ) treatment to identify the role of TLR4 in different cell types in the development of the proinflammatory state during DR. TLR4 mutation did not block the occurrence of high blood glucose after STZ injection compared with WT mice but did alleviate the progression of DR and alter the expression of the small vessel proliferation-related genes, vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1α (HIF-1α). Grafting bone marrow-derived cells from TLR4 WT mice into TLR4 mutant mice increased the levels of TNF-α, IL-1β, and MIP-2 and increased the damage to the retina. Similarly, VEGF and HIF-1α expression were restored by the bone marrow transplantation. These findings identify an essential role for TLR4 in bone marrow-derived cells contributing to the progression of DR.

Highlights

Diabetic retinopathy (DR) is one of the most common microangiopathic complications of patients with diabetes mellitus (DM) [1]
Its core pathological process is elicited by inflammatory injury to the vascular endothelial cells in the retina, which is followed by the angiogenesis of small vessels in the early stage [3,4,5]
Chimeric mice were produced by transferring donor bone marrow cells into irradiated recipient animals using combinations of toll-like receptor 4 (TLR4) wild type (WT) and mutant type (Mut) mice in the following donor/recipient groups: WT/WT, WT/Mut, Mut/Mut, and Mut/WT (Figure 1)

Summary

Introduction

Diabetic retinopathy (DR) is one of the most common microangiopathic complications of patients with diabetes mellitus (DM) [1]. Chimeric mice were produced by transferring donor bone marrow cells into irradiated recipient animals using combinations of TLR4 wild type (WT) and mutant type (Mut) mice in the following donor/recipient groups: WT/WT, WT/Mut, Mut/Mut, and Mut/WT (Figure 1). The mortality reached 29.17% after 4 months [1 mouse in the WT/WT group died at 31 weeks and 2 mice in each of the other 3 groups died during the last week (7/24)] without the subcutaneous injection of insulin to control the blood glucose levels.

Results

Conclusion