Diesel exhaust particles disrupt blood-retina barrier integrity via TLR2 and TLR4 activation.

Abstract

Diesel exhaust particles (DEPs), a major component of air pollution, are well-known to induce inflammation and vascular dysfunction. However, the molecular mechanisms linking DEP exposure to the disruption of the blood-retina barrier (BRB) remain poorly understood. Toll-like receptors (TLRs), particularly TLR2 and TLR4, play critical roles in inflammatory signaling and may contribute to DEP-induced retinal endothelial dysfunction. This study investigates the involvement of TLR2 and TLR4 in mediating DEP-induced disruption of the BRB and evaluates the protective effects of TLR inhibition using both in vitro and in vivo experiments. U937 human macrophages were exposed to DEPs of ultrafine size (＜0.2 μm), and the mRNA expression of TNF-α and IL-1β was quantified. Conditioned media from DEP-exposed U937 cultures were then used to treat human retinal endothelial cells (HRECs). DEP exposure significantly increased TNF-α and IL-1β mRNA expression in U937 macrophages. Conditioned media from DEP-exposed U937 macrophages reduced claudin-5 and ZO-1 expression in HRECs, resulting in increased BRB permeability. Inhibition of TLR2 and TLR4 using C29 and TAK242, respectively, significantly attenuated TNF-α and IL-1β mRNA expression in DEP-exposed U937 macrophages and preserved BRB integrity by maintaining claudin-5 and ZO-1 expression in HRECs. In the mouse model, DEP exposure caused a marked reduction in claudin-5 and ZO-1 levels in retinal vessels, whereas treatment with C29 and TAK242 mitigated the loss of these tight junction proteins. This study demonstrates that DEPs induce inflammation and BRB dysfunction through TLR2 and TLR4 activation, leading to increased vascular permeability and potential retinal damage. Furthermore, TLR2 and TLR4 inhibition may be a promising therapeutic strategy to protect retinal health from air pollution-induced damage.