Müller Cell–Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy

Diabetic retinopathy (DR) is the most common complication of diabetes and a leading cause of vision loss worldwide (1). Unfortunately, there are no treatments targeting early stages of the disease prior to the onset of sight-threatening vascular defects such as macular edema or neovascularization. A better understanding of the etiology of DR is needed to identify therapeutic targets to halt early disease progression. To this end, numerous studies demonstrated that a low-grade inflammation occurs in retinas of diabetic animal models and suggest that inflammation contributes a role in DR progression. Various mechanisms leading to retinal inflammation in DR have been described, with the majority of studies implicating retinal Muller glial cells and microglia as the initiators of retinal inflammation (for review, see ref. 2). However, seldom does a study make a strong connection between these two cell types. In this issue of Diabetes , Portillo et al. (3) describe a mechanism in which retinal inflammation in diabetic mice is dependent upon expression of the cluster of differentiation gene 40 (CD40) receptor by Muller cells (Fig. 1). The study suggests that CD40 activation induces Muller cells to release ATP, leading to activation of P2X7 purinergic receptors on retinal microglia and their subsequent expression of inflammatory cytokines. Importantly, the requirement of Muller cell–specific CD40 expression to recapitulate the appearance of acellular capillaries in diabetic retinas also suggests that inflammation is necessary for the loss of vascular cells associated with DR pathology.