The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated ...The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.展开更多
基金funded by the National Natural Science Foundation of China(Nos.8197219382171003).
文摘The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.
