Abstract
Purpose :
Müller cells play a central role in development of retinal complications through the production of pro-angiogenic and pro-inflammatory cytokines. This study investigated molecular events that lead to Müller cell gliosis and release of pro-angiogenic and pro-inflammatory cytokines in response to diabetes. Specifically, we evaluated a role for spleen tyrosine kinase (SYK) in activation of the transcription factors hypoxia-inducible factor 1 (HIF1) and nuclear factor κB (NF-κB).
Methods :
Diabetes was induced in mice by administration of low-dose streptozotocin. Retinas were analyzed after 6 or 16 weeks of diabetes. Human MIO-M1 Müller cell cultures were exposed to either hyperglycemic conditions, hypoxic conditions, or medium supplemented with TNFα. SYK suppression was achieved by pharmacological inhibition or genetic knockdown.
Results :
SYK activation was observed in the retina of diabetic mice coincident with increased expression of HIF-1α, activation of NF-κB, and macrophage infiltration of the inner retina. In Müller cell cultures exposed to hypoxic conditions, SYK activity was required for increased expression of both HIF-1α and the pro-angiogenic cytokines VEGF and ANGPTL4. In Müller cell cultures exposed to either hyperglycemic conditions or TNFα, NF-κB was activated and expression of pro-inflammatory cytokines IL-1β and IL6 was increased. SYK was also required for both NF-κB activation and increased inflammatory cytokine expression in cells exposed to TNFα.
Conclusions :
The results support a role for SYK activation as a unifying mechanism for increased expression of pro-angiogenic and pro-inflammatory cytokines by Müller glia in response to diabetes.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.