Abstract:
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-1β (IL-1β) production in bone-marrow-derived 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-1β 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 lipopolysaccharide-induced 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.
摘要:
虽然抗生素是专门针对细菌的,已知大多数影响宿主细胞生理学。据报道,某些类别的抗生素具有免疫抑制作用,但是潜在的机制仍然难以捉摸。这里,我们发现强力霉素,核糖体靶向抗生素(RAbo),有效抑制骨髓源性巨噬细胞(BMDMs)中线粒体翻译和核苷酸结合域以及富含亮氨酸的重复序列蛋白3(NLRP3)炎症体介导的caspase-1激活和白介素1β(IL-1β)的产生。此外,线粒体甲硫氨酰-tRNA甲酰基转移酶(Mtfmt)的敲低,这是线粒体翻译的速率限制,还导致NLRP3炎性体介导的caspase-1激活和IL-1β分泌的抑制。此外,多西环素处理和Mtfmt敲除都阻断了线粒体DNA(mtDNA)的合成和氧化mtDNA(ox-mtDNA)的生成,作为NLRP3炎性体激活的配体。此外,体内结果表明,多西环素减轻NLRP3炎性体依赖性炎症,包括脂多糖诱导的全身性炎症和子宫内膜炎。一起来看,结果揭示了靶向有丝分裂体的抗生素能够通过抑制线粒体翻译和mtDNA合成来减轻NLRP3炎性体激活,从而为治疗NLRP3相关疾病开辟了新的可能性.