TY - JOUR
T1 - Inflammasome activation induces pyroptosis in the retina exposed to ocular hypertension injury
AU - Pronin, Alexey
AU - Pham, Dien
AU - An, Weijun
AU - Dvoriantchikova, Galina
AU - Reshetnikova, Galina
AU - Qiao, Jianzhong
AU - Kozhekbaeva, Zhanna
AU - Reiser, Ashlyn E.
AU - Slepak, Vladlen Z.
AU - Shestopalov, Valery I.
N1 - Funding Information:
We thank Drs. J. Lieberman and H. Wu for expert advice on pyroptosis detection and blockade; Dr. P. de Rivero Vaccari for consultations on inflammasome analysis in the retina, Dr. E. Ivanova for advising us on retinal whole-mount immunostaining, Mrs. J. Arcury for help with confocal microscopy, Mrs. J. Shestopalov for the help with digital art and Ms. J. Dennison for reading and discussing the manuscript. Funding. This work was supported by National Institute of Health (National Eye Institute) grants RO1EY018666 (VZS), R01EY021517 (VIS), Research to Prevent Blindness foundation Career Development Award (VIS), National Institute of Health P30 center grant EY014801, an unrestricted Research to Prevent Blindness and US Department of Defense grant W81XWH-13-1-0048 and the Department of Ophthalmology and Russian Science Foundation grant N17-15-01433 (to VIS).
Funding Information:
This work was supported by National Institute of Health (National Eye Institute) grants RO1EY018666 (VZS), R01EY021517 (VIS), Research to Prevent Blindness foundation Career Development Award (VIS), National Institute of Health P30 center grant EY014801, an unrestricted Research to Prevent Blindness and US Department of Defense grant W81XWH-13-1-0048 and the Department of Ophthalmology and Russian Science Foundation grant N17-15-01433 (to VIS).
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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 Pannexin1 (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 (WT) 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.
AB - 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 Pannexin1 (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 (WT) 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.
KW - Caspase-1 (ICE)
KW - Inflammasome
KW - Ischemia
KW - Mechanical stress
KW - Pannexins
KW - Pyroptosis
KW - Retina
UR - http://www.scopus.com/inward/record.url?scp=85064223693&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064223693&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2019.00036
DO - 10.3389/fnmol.2019.00036
M3 - Article
AN - SCOPUS:85064223693
VL - 12
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
SN - 1662-5099
M1 - 36
ER -