Many studies have demonstrated that there was a close connection between autophagy and pyroptosis in multiple physiological and pathological processes.
37–39 Autophagy could effectively inhibit the activation of the NLRP3 inflammasome by eliminating damaged mitochondria and reducing the accumulation of reactive oxygen species, subsequently leading to the suppression of the canonical pathway of pyroptosis activation.
39 Our previous research established that dry eye is associated with oxidative stress-induced autophagy irregularities.
16 Previous studies have reported that perturbation of intracellular potassium homeostasis with the potassium-selective ionophore valinomycin promotes autophagy in several cell types.
40 Autophagy blocks pyroptosis through elimination of DAMPs and PAMPs and directly targeting the essential components involved in this process.
41 In this investigation, our findings indicate an upregulation in the activity of the potassium channel KCNK5 under desiccating stress conditions. Concurrently, cellular activity was compromised, resulting in an escalation of cell pyroptosis. Subsequent downregulation of KCNK5 led to the restoration of autophagy and a subsequent decrease in cell pyroptosis. Hence, we postulated that the heightened potassium channel activity in corneal epithelial cells under desiccation conditions led to compromised autophagy, subsequently inducing pyroptosis in corneal epithelial cells. In this study, we present the novel finding that TNFSF10 promotes autophagy, thereby mitigating corneal epithelial pyroptosis in dry eye. TNFSF10 is a member of tumor necrosis factor family, which could exert its anti-inflammatory effects by direct inhibition of T-cell activation.
42 Some studies have reported that TNFSF10 could induce autophagy in cancer cells.
25,43 Lin et al. reported that the RIPK1-mediated MAPK8/JNK activation serves as the upstream signaling pathway responsible for TNFSF10-induced cytoprotective autophagy.
44 In this study, we demonstrated that TNFSF10 was the downstream target of KCNK5. The precise regulatory mechanisms through which KCNK5 influences TNFSF10 expression and the underlying signaling pathways by which TNFSF10 modulates autophagy warrant further investigation. Our prior investigation has substantiated that the modulation of the IFN-γ pathway effectively inhibits pyroptosis in corneal epithelial cells, thereby leading to the restoration of tear secretion.
8 Lu et al. reported that the administration of LYN-1604, an autophagy activator, resulted in the downregulation of ocular surface inflammation and a concomitant increase in tear production.
45 These findings suggest a nuanced and intricate interplay between ocular inflammation and the function of the lacrimal gland. Consequently, we posit that the inhibition of KCNK5 and the administration of rhTNFSF10 in dry eye mice may serve to mitigate ocular inflammation, suppress pyroptosis in lacrimal glands, and ultimately restore tear secretion. The investigation of the specific molecular mechanisms governing the influence of ocular surface inflammation on tear secretion remains an imperative avenue for future research.