期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 210, 期 -, 页码 75-84出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2023.11.014
关键词
NLRP3 inflammasome; Doxycycline; Mitochondrial translation; mtDNA
This study reveals that the antibiotic doxycycline effectively inhibits NLRP3 inflammasome activation by targeting mitochondrial translation and mtDNA synthesis, offering potential for the treatment of NLRP3-related diseases.
While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1 beta (IL-1 beta) production in bone-marrowderived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1 beta secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharideinduced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.
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