Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 22, Issue 5, Pages 1362-1371Publisher
WILEY
DOI: 10.1111/ajt.16968
Keywords
animal models; basic (laboratory) research; science; corneal transplantation; ophthalmology; cytokines; cytokine receptors; immune regulation; immunosuppression; immune modulation; innate immunity; macrophage; monocyte biology; murine; organ transplantation in general; translational research; science
Categories
Funding
- Innovation Project of Shandong Academy of Medical Sciences
- Shandong Provincial Excellent Innovation Team Program
- Taishan Scholars Program [201812150, 202103185]
- Natural Science Foundation of Shandong Province [ZR2020MH175]
- National Nature Science Foundation of China [81870639, 82070923, 81570821, 81900907]
- Academic Promotion Programme of Shandong First Medical University [2019RC009, 2019PT002, 2019ZL001]
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Enhanced autophagy can alleviate corneal allograft rejection by inhibiting NLRP3 inflammasome activity through NLRP3 degradation. Blocking autophagy restores NLRP3 inflammasome activity, suggesting that autophagy plays a critical role in treating corneal allograft rejection.
Autophagy has been reported to be involved in many aspects of innate and adaptive immunity. Manipulating autophagy is recognized as a promising therapeutic approach for treating immunological diseases, including allograft rejection, and graft-versus-host disease. However, whether autophagy was closely associated with the pathogenesis of corneal allograft rejection remains largely unknown. Here, we showed that rapamycin (RAPA)-induced autophagy alleviated corneal allograft rejection. By contrast, blocking autophagic activity using 3-methyladeine (3-MA) aggravated corneal transplantation rejection. Mechanistically, we revealed that the enhanced autophagic turnover by RAPA inhibited NLRP3 inflammasome activity through NLRP3 degradation. While blocking the fusion of autophagosomes with lysosomes by bafilomycin A1(BafA1), the reduced NLRP3 inflammasome activity induced by RAPA was significantly restored, with increased protein levels of NLRP3 and cleaved Casp-1(p10), as well as IL-1 beta secretion. Moreover, we further revealed that pharmacologically blocking NLRP3 inflammasome signaling prolonged the survival of corneal allografts. Taken together, these findings underscored the critical roles of enhanced autophagy in treating corneal allograft rejection, which provided an alternative intervention strategy to control corneal transplantation rejection.
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