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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00036

Inflammasome activation induces pyroptosis in the retina exposed to ocular hypertension injury.

 Alexey Pronin1,  Dien Pham2, Weijun An2, Galina Dvoriantchikova2, Galina F. Reshetnikova3,  Qiao Jianzhong2,  Zhanna Kozhekbaeva4, Ashlyn E. Reiser5, Vladlen Z. Slepak1 and  Valery I. Shestopalov2, 6, 7*
  • 1Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, United States
  • 2Bascom Palmer Eye Institute, University of Miami Health System, United States
  • 3University of Miami, United States
  • 4Department of Cell Biology, Leonard M. Miller School of Medicine, United States
  • 5Geisinger Commonwealth School of Medicine, United States
  • 6Institute for Information Transmission Problems (RAS), Russia
  • 7Department of Cell Biology, Leonard M. Miller School of Medicine, United States

Mechanical stress and hypoxia during episodes of ocular hypertension (OHT) trigger glial activation and neuroinflammation in the retina. Glial activation and release of pro-inflammatory cytokines TNFα and IL-1β, complement, and other danger factors was shown to facilitate injury and loss of retinal ganglion cells (RGCs) that send visual information to the brain. However, cellular events linking neuroinflammation and neurotoxicity remain poorly characterized. Several pro-inflammatory and danger signaling pathways, including P2X7 receptors and Panx1 channels, are known to activate inflammasome caspases that proteolytically activate gasdermin D channel-formation to export IL-1 cytokines and/or induce pyroptosis. In this work, we used molecular and genetic approaches to map and characterize inflammasome complexes and detect pyroptosis in the OHT-injured retina. Acute activation of distinct inflammasome complexes containing NLRP1, NLRP3 and Aim2 sensor proteins was detected in RGCs, retinal astrocytes and Muller glia of the OHT-challenged retina. Inflammasome-mediated activation of caspases-1 and release of mature IL-1β were detected within 6 h and peaked at 12-24 h after OHT injury. These coincided with the induction of pyroptotic pore protein gasdermin D in neurons and glia in the ganglion cell layer (GCL) and inner nuclear layer (INL). The OHT-induced release of cytokines and RGC death were significantly decreased in the retinas of Casp1-/-Casp4(11)del, Panx1-/- and in wild-type mice treated with the Panx1 inhibitor probenecid. Our results showed a complex spatio-temporal pattern of innate immune responses in the retina. Furthermore, they indicate an active contribution of neuronal NLRP1/NLRP3 inflammasomes and the pro-pyroptotic gasdermin D pathway to pathophysiology of the OHT injury. These results support the feasibility of inflammasome modulation for neuroprotection in OHT-injured retinas.

Keywords: Retina, Inflammasome, Mechanical Stress, Ischemia, pannexins, Caspase-1 (ICE), pyroptosis

Received: 25 Aug 2018; Accepted: 29 Jan 2019.

Edited by:

Juan A. Orellana, Pontificia Universidad Católica de Chile, Chile

Reviewed by:

Rebecca M. Sappington, Vanderbilt University Medical Center, United States
Claudio Bucolo, Università degli Studi di Catania, Italy  

Copyright: © 2019 Pronin, Pham, An, Dvoriantchikova, Reshetnikova, Jianzhong, Kozhekbaeva, Reiser, Slepak and Shestopalov. 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) and the copyright owner(s) 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: Prof. Valery I. Shestopalov, Bascom Palmer Eye Institute, University of Miami Health System, Miami, United States,