Inhibition of Dectin-1 alleviates inflammation in early diabetic retinopathy by regulating microglia phenotype

Diabetic retinopathy (DR) is a major factor in vision loss in diabetic patients, triggering a series of pathological changes. At present, the treatment methods for diabetic retinopathy are limited. There is an urgent need to further explore its mechanism to bring more treatment options to patients.There is increasing evidence that microglia activation plays a crucial role in inflammatory DR. The C type lectin receptor Dectin-1 is known to play an important role in the inflammatory regulation of microglia, however, its role and mechanism in DR remains unclear. This study aims to elucidate the possible mechanisms through which Dectin-1 influences the inflammatory response in high glucose(HG) stimulated microglia and its impact on retinal inflammation during the early stages of DR.

Human microglial cells (HMC3) were stimulated with HG (25 mmol/L), and a streptozotocin (STZ)induced C57BL/6J mouse model was established to simulate DR. To investigate the role of Dectin-1 in HMC3 cells and its underlying molecular mechanisms, we employed western blotting, quantitative realtime PCR (qRT-PCR), hematoxylineosin (H&E) staining, and immunofluorescence analysis.

Our findings revealed that Dectin-1 levels were elevated in microglia stimulated by HG, playing a pivotal role in cell polarization and the induction of inflammatory factors in vitro. In vivo experiments conducted on STZ induced diabetic mice demonstrated an increased expression of Dectin-1 in retinal tissues. This elevation further promoted the expression of pro inflammatory factors, such as TNF-α, IL-1β, and iNOS, triggering an inflammatory response and causing damage to the retina. Notably, inhibiting Dectin-1 reversed these detrimental effects, ultimately contributing to the delay in the progression of DR. Our investigation also uncovered a significant interaction between Dectin-1 and the downstream pro-inflammatory pathway NF-κB. This interaction occurred through the activation of spleen tyrosine kinase (Syk), both in vitro and in vivo.

In summary, our research strongly suggests that Dectin-1 plays a crucial pro-inflammatory role in early DR. This mechanismis, at least in part, mediated through the Syk/NF-κB pathway. Consequently, inhibition of Dectin-1 is expected to become a potential therapeutic target for delaying DR.