STAT3 activation in circulating myeloid-derived cells contributes to retinal microvascular dysfunction in diabetes

Area of Science:

• Ophthalmology
• Immunology
• Endocrinology

Background:

• Leukostasis, characterized by capillary occlusion, is a key event in diabetic retinopathy (DR).
• Circulating monocytes are implicated in retinal vessel occlusion during diabetes.
• The role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and retinal microvascular damage was investigated.

Purpose of the Study:

• To investigate the role of the STAT3 pathway in diabetes-induced immune cell activation.
• To determine the contribution of STAT3 pathway activation to retinal microvascular degeneration in diabetic retinopathy.
• To explore the involvement of STAT3 in the initiation of DR in type 1 diabetes (T1D).

Main Methods:

• Flow cytometry was used to evaluate phosphorylated STAT3 (pSTAT3) and immune cell markers in circulating leukocytes from T1D patients and diabetic mice.
• Real-time RT-PCR assessed suppressor of cytokine signalling 3 (SOCS3) expression.
• Cytometric Bead Array measured plasma cytokine levels.
• Retinal leukostasis and acellular capillaries were examined in wild-type and genetically modified diabetic mice.

Main Results:

• Increased pSTAT3 expression was observed in leukocytes from T1D patients with mild non-proliferative diabetic retinopathy (mNPDR).
• Diabetic mice showed elevated pSTAT3 and SOCS3 expression in leukocytes, along with increased plasma IL-6 and CCL2.
• Genetic deletion of SOCS3 in myeloid cells (LysM^Cre/+SOCS3^fl/fl mice) exacerbated leukocyte activation, retinal leukostasis, and acellular capillaries in diabetic mice.

Conclusions:

• STAT3 activation in circulating immune cells is linked to retinal microvascular degeneration.
• The STAT3 pathway may play a role in the initiation of diabetic retinopathy in T1D.
• Targeting the STAT3 pathway could offer therapeutic potential for managing diabetic retinopathy.