Annexin A1 as a Key Modulator of Inflammatory, Glial, and Angiogenic Signaling Pathways in Diabetic Retinopathy

Purpose: Annexin A1 (AnxA1) regulates inflammation and neovascularization in ocular diseases, influencing growth factor signaling and cytoskeletal dynamics. Accordingly, this study aimed to investigate the role of the AnxA1 protein in diabetic retinopathy (DR) and to understand how its absence affects inflammation and vascular dysfunction in DR. Methods: DR model was induced 12 weeks after streptozotocin injection in wild-type (AnxA1+/+) and AnxA1 knockout (AnxA1-/-) mice. We evaluated the consequences of AnxA1 deficiency on retinal morphology, Müller cell activation, inflammation, and angiogenesis associated with DR. We also performed an in silico analysis in wild-type animals with DR induced for 6 weeks and in a dataset of patients with DR. Furthermore, a choroidal neovascularization model was used to evaluate the role of AnxA1 in angiogenesis signaling. Results: AnxA1 deficiency exacerbated selective systemic inflammatory alterations and promoted retinal neurodegeneration associated with DR. AnxA1-/- diabetic animals exhibited increased circulating IL-6, IL-17, chemokine (C-X-C motif) ligand 1, and monocyte chemoattractant protein-1 levels, retinal monocyte chemoattractant protein-1 and IL-4 upregulation, dysregulated MAPK/STAT3 signaling, and altered gliosis responses. In addition, AnxA1 deficiency was associated with a proangiogenic signaling profile characterized by increased retinal levels of EGF, VEGF-A, and endothelin-1 in DR, whereas the upregulation of VEGF-C was predominantly observed in the choroidal neovascularization model. Conclusions: Endogenous AnxA1 modulates inflammatory-glial and proangiogenic signaling pathways in the diabetic retina. Its deficiency is associated with selective inflammatory dysregulation and enhanced angiogenesis-related signaling during DR progression.