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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.
Sec. Signaling
Volume 12 - 2024 | doi: 10.3389/fcell.2024.1467799
This article is part of the Research Topic Editors’ Showcase 2023: Insights in Signaling View all 4 articles

Interleukin-1 Receptor-Dependent and -Independent Caspase-1 Activity in Retinal Cells Mediated by Receptor Interacting Protein 2

Provisionally accepted
Susanne Mohr Susanne Mohr *Brandon A. Coughlin Brandon A. Coughlin Barbara Christian Barbara Christian Brett Trombley Brett Trombley
  • Michigan State University, East Lansing, United States

The final, formatted version of the article will be published soon.

    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.

    Keywords: Diabetic Retinopathy, Müller cells, Retinal inflammation, caspase-1, Interleukin-1beta, Receptor interacting protein 2

    Received: 20 Jul 2024; Accepted: 23 Sep 2024.

    Copyright: © 2024 Mohr, Coughlin, Christian and Trombley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Susanne Mohr, Michigan State University, East Lansing, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.