Glia. 2026 Jun;74(6):e70155. doi: 10.1002/glia.70155.
ABSTRACT
It is well established that inflammation contributes to the ocular complications caused by diabetes; however, the specific molecular events that drive diabetes-induced pro-inflammatory signaling in the retina remain to be fully elucidated. This study investigated the role of Müller glial spleen tyrosine kinase (SYK) in diabetes-induced retinal complications. Hyperglycemic culture conditions increased mitochondrial membrane permeability and cytosolic mitochondrial DNA content in human MIO-M1 Müller cells and enhanced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, nuclear factor-κB (NF-κB) activation, and inflammatory cytokine expression. STING inhibition reduced inflammatory cytokine expression in cells exposed to hyperglycemic conditions by acting downstream of the increase in cytosolic mitochondrial DNA levels. In cells exposed to either hyperglycemic conditions or the STING agonist diABZI, SYK signaling was necessary for cGAS-STING pathway activation. Inhibition of SYK-dependent cGAS-STING signaling reduced the expression of inflammatory cytokines, including IL1β, CCL2, and CCL5, under hyperglycemic conditions. In the retina of diabetic mice, Müller glia-specific SYK deletion reduced glial activation and attenuated inflammatory cytokine expression. Müller glia-specific SYK deletion also prevented diabetes-induced retinal thinning and visual function deficits in spatial frequency threshold and contrast sensitivity. The data support an essential role for Müller glial SYK in diabetes-induced retinal inflammation and the development of functional deficits in vision.
PMID:41972434 | DOI:10.1002/glia.70155