Enhanced autophagy alleviated corneal allograft rejection via inhibiting NLRP3 inflammasome activity

Abstract

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‐1β 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.

Characterization and Evaluation of Rapamycin-Loaded Nano-Micelle Ophthalmic Solution

“…We successfully developed RAPA-NM and demonstrated its good solubility, stability, and bioavailability. These findings are supported by a previous study, which reported that PVCL-PVA-PEG micelles loaded myricetin with excellent solubility and stability, improved permeation, and showed no irritation or toxicity [ 20 ]. Moreover, several RAPA nano-formulations have been developed using polylactic acid (PLA), poly lactic-co-glycolic acid (PLGA), and Eudragit RS with particle sizes ranging from 180 nm to 280 nm [ 47 , 48 ].…”

“…Graft rejection is the main reason for corneal transplantation failures, and the underlying mechanism remains largely unknown [ 52 ]. Our previous findings depicted the advantageous anti-rejection effect of RAPA-NM both in the murine corneal transplantation model and rabbit high-risk corneal transplantation model [ 19 , 20 ], which underscored its promising application prospects. Nevertheless, its anti-rejection mechanism has not yet been systemically investigated.…”

“…Polymeric micelles have aroused great concern due to their potential to overcome anatomical barriers, as well as reduce toxicity, and increase ocular retention [ 16 , 17 , 18 ]. In our previous study, the RAPA-loaded nano-micelle ophthalmic solution (RAPA-NM), fabricated by encapsulation of RAPA into a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL-PVA-PEG) graft copolymer, had an excellent anti-corneal allograft rejection outcome [ 19 , 20 ]. Nonetheless, the physicochemical properties, biocompatibility, and underlying anti-rejection mechanism of RAPA-NM have not yet been sufficiently explored; therefore, we aimed to further evaluate these properties and pave the way for its application.…”

The NLRP3 Inflammasome Is Required for Protection Against Pseudomonas Keratitis

“…Several studies have investigated the role of NLRP3 inflammasome pathway in the noninfectious inflammatory disorders of the cornea. These studies have shown that: (i) inhibiting NLRP3 inflammasome: (a) remarkably prolongs the survival of corneal allografts 32 , 33 and (b) improves corneal wound healing after alkali burn, 34 and that (ii) the advanced glycation end products (AGEs)/ROS/NLRP3 inflammasome axis contributes to delayed diabetic corneal wound healing and nerve regeneration. 35 …”

The multifunctional roles of autophagy in the innate immune response: Implications for regulation of transplantation rejection

“…Interestingly, another research group showed that ATG5 also participated in antibody-mediated rejection during kidney grafts, which suggested that Atg5-mediated autophagy could affect graft survival through multiple pathways ( Cheng et al, 2021 ). Recently, a study suggested rapamycin, an autophagy activator, enhanced autophagy and alleviated corneal allograft rejection ( Wei et al, 2022 ). Mechanistically, the enhanced autophagic turnover by rapamycin inhibited NLRP3 inflammasome, cleaved Casp-1(p10), and IL-1β through NLRP3 degradation.…”