Modulation of p75^NTR prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats

Aims/hypothesis: Diabetic retinopathy is characterised by early blood-retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75^NTR), suggesting a possible pathological role of the proNGF-p75^NTR axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75^NTR would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown. Methods: Diabetes was induced by streptozotocin in wild-type and p75^NTR knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75^NTR short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Müller glial cell line (rMC-1) and primary Müller cells. Results: Deletion of p75^NTR blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75^NTR also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75^NTR blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75 ^NTR-dependent production of inflammatory mediators in primary wild-type Müller and rMC-1 cultures, but not in p75KO Müller cells. Conclusions/interpretation: The proNGF-p75^NTR axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75^NTR as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.