Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

Abstract

Purpose Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes. Methods RiboTag ( Pdgfra -cre;HA-Rpl22) mice were used to compare the impact of streptozotocin (STZ) and a high-fat, high-sucrose (HFHS) diet on ribosome association of mRNAs in Müller glia by RNA sequencing analysis. Human MIO-M1 Müller cells were exposed to either hyperglycemic or hypoxic culture conditions. Genetic manipulation and pharmacologic inhibition were used to interrogate signaling pathways. Results Association of mRNAs encoding triggering receptor expressed on myeloid cells 2 (TREM2), DNAX-activating protein 12 kDa (DAP12), and colony stimulating factor 1 receptor (CSF1R) with ribosomes isolated from Müller glia was upregulated in both STZ diabetic mice and mice fed an HFHS diet. The TREM2/DAP12 receptor-adaptor complex signals in coordination with CSF1R to activate spleen tyrosine kinase (SYK). SYK activation was enhanced in the retina of diabetic mice and in human MIO-M1 Müller cell cultures exposed to hyperglycemic or hypoxic culture conditions. DAP12 knockdown reduced SYK autophosphorylation in Müller cells exposed to hyperglycemic or hypoxic conditions. SYK inhibition or DAP12 knockdown suppressed hypoxia-induced expression of the transcription factor hypoxia-inducible factor 1⍺ (HIF1⍺), as well as expression of vascular endothelial growth factor and angiopoietin-like 4. Conclusions The findings support TREM2/DAP12 receptor-adaptor complex signaling via SYK to promote HIF1α stabilization and increased angiogenic cytokine production by Müller glia.

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“…Triggering receptor expressed on myeloid cells 2/DNAX activating protein of 12 kDa (TREM2/DAP12) signaling promotes the proliferation, migration, and phagocytosis of apoptotic neurons in microglia (Konishi and Kiyama 2018 ). In addition, upregulation of TREM2/DAP12 via SYK increases proangiogenic cytokines in Müller cells, which contributes to diabetic retinopathy progression (Yerlikaya et al 2022 ). Both upregulation of tyrobp and syk might be involved in the glial activation and be associated with chronic retinopathy in EAE.…”