AUTHOR=Coughlin Brandon A. , Christian Barbara , Trombley Brett , Mohr Susanne 

TITLE=Interleukin-1 receptor-dependent and -independent caspase-1 activity in retinal cells mediated by receptor interacting protein 2

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 12 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1467799

DOI=10.3389/fcell.2024.1467799

ISSN=2296-634X

ABSTRACT=Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation in vitro and in vivo. Our in vivo results demonstrate that caspase-1 activation progresses from an IL-1 receptor (IL-1R1) independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of STZ (streptozotocin) mice. A similar hyperglycemia-mediated caspase-1/IL-1b/IL-1R1 feedback signaling was detected in vitro in human Müller cells which was prevented by treatment with an IL-1 receptor antagonist (IL-1ra). Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1b sustains caspase-1 activation via caspase-1/IL-1b/IL-1R1 feedback and we identified Receptor Interacting Protein-2 (RIP2) as mediator of both hyperglycemiaand IL-1b-induced caspase-1 activation. Activation of caspase-1/IL-1b/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown. We conclude that any intervention in caspase-1/IL-1b/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.