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Goal: Study the role of CD40-TRAF signaling in promoting various events critical to de development of diabetic retinopathy.
Goal: Study the role of CD40-TRAF signaling in promoting various events critical to de development of diabetic retinopathy.
Diabetic retinopathy is the leading cause of blindness in working age adults in US. We demonstrated that CD40 is a central mediator of inflammatory responses in the diabetic retina and is required for development of diabetic retinopathy (Figure 1).
Figure 1
Vos S, Portillo J-A C, Hubal A, Bapputty R, Pfaff A, Aaron R, Weng M, Sun D, Lu Z-R, Yu J-S and Carlos S. Subauste CS. CD40 induces unfolded protein response, upregulation of VEGF and vascular leakage in diabetic retinopathy. Diabetes 2025.
CD40-TRAF2,3 - PLCY1 signaling activates UPR sensors in Müller cells and stimulates expression of VEGF in vitro and in vivo in the diabetic retina (Figure 1).. A CD40-TRAF2,3 blocking peptide inhibits UPR activation, VEGF upregulation and vascular leakage. CD40-TRAF2,3 signaling is also known to trigger PLCY 1-dependent activation of ATP-P2X7-pro-inflammatory cytokine production and PLCY1-independent CCL2 production by Muller cells, events that likely contribute to vascular leakage.
Using transgenic Cd40-/- mice with selective rescue of CD40 in retinal Muller cells, we uncovered a CD40 → ATP → P2X7 pathway that drives inflammatory responses, activation of the unfolded protein response (UPR) and upregulation of VEGF in the diabetic retina (Figure 1). Using transgenic mice generated in the lab, we also showed that disruption of CD40-TRAF2,3 signaling ablates retinal inflammation, UPR activation, and prevents the development of diabetic retinopathy. We developed and patented a cell-permeable CD40-TRAF2,3 blocking peptide as a pharmacologic approach to block CD40-TRAF2,3 signaling. This peptide has retro-inverso features making it resistant to degradation by peptidases. We reported that intravitreal administration of the CD40-TRAF2,3 peptide to diabetic mice ablates the inflammatory responses, UPR activation, VEGF upregulation, and vascular leakage in diabetic mice. We are currently using transgenic mice to examine the role of CD40 in various other processes that are key to the development of diabetic retinopathy.
Publications
Vos S, Portillo J-A C, Hubal A, Bapputty R, Pfaff A, Aaron R, Weng M, Sun D, Lu Z-R, Yu J-S and Carlos S. Subauste CS. CD40 induces unfolded protein response, upregulation of VEGF and vascular leakage in diabetic retinopathy. Diabetes 2025.
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