Abstract
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.
Highlights
Hypoxia and mechanical stretch during episodes of ocular hypertension (OHT) induce neuroinflammation in the retina and optic nerve
No IL-1β release was detected in normotensive control eye of Panx1−/− or Casp1−/−Casp4(11)del mice (CaspDKO, Figure 1A, dotted yellow line)
We demonstrate that activation of the inflammasome and release of IL-1β in the retina occur within a few hours after OHT injury
Summary
Hypoxia and mechanical stretch during episodes of ocular hypertension (OHT) induce neuroinflammation in the retina and optic nerve. Pro-inflammatory cytokines, including the IL-1 family, are produced by glial, microglial and neuronal cells in the retina in response to ischemic injury and in glaucoma (Yoneda et al, 2001; Ivanov et al, 2006, 2008; Namekata et al, 2009; Qi et al, 2014). Their production is controlled by inflammasome activation and significantly increased after exposure to OHT (Barakat et al, 2012; Chi et al, 2014). Genetic ablation and/or pharmacological inhibition of caspase-1 or inflammasome regulators, including Panx, IL-1 or P2X receptors was shown to protect retinal neurons in several injury paradigms (Yoneda et al, 2001; Zhang and Chintala, 2004; Arai et al, 2006; Pelegrin et al, 2008; Seki et al, 2009; Dvoriantchikova et al, 2012; Puyang et al, 2016)
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