PMID- 37992790
OWN - NLM
STAT- MEDLINE
DCOM- 20231222
LR  - 20240217
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 210
DP  - 2024 Jan
TI  - Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting 
      mitochondrial DNA synthesis.
PG  - 75-84
LID - S0891-5849(23)01115-2 [pii]
LID - 10.1016/j.freeradbiomed.2023.11.014 [doi]
AB  - 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-1beta (IL-1beta) 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-1beta 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.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Liu, Suyuan
AU  - Liu S
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - Tan, Meiling
AU  - Tan M
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - Cai, Jiangxue
AU  - Cai J
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - Li, Chenxuan
AU  - Li C
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - Yang, Miaoxin
AU  - Yang M
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - Sun, Xiaoxiao
AU  - Sun X
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China.
FAU - He, Bin
AU  - He B
AD  - Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and 
      Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, 
      Nanjing, 210095, PR China; MOE Joint International Research Laboratory of Animal 
      Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, PR China. 
      Electronic address: heb@njau.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231120
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Inflammasomes)
RN  - 0 (Anti-Bacterial Agents)
RN  - N12000U13O (Doxycycline)
RN  - 0 (DNA, Mitochondrial)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - 0 (Interleukin-1beta)
SB  - IM
MH  - Female
MH  - Animals
MH  - Mice
MH  - *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
MH  - *Inflammasomes/genetics/metabolism
MH  - Anti-Bacterial Agents/pharmacology
MH  - Doxycycline
MH  - Inflammation/drug therapy/genetics
MH  - DNA, Mitochondrial/genetics/metabolism
MH  - Caspase 1/metabolism
MH  - Ribosomes/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Mice, Inbred C57BL
OTO - NOTNLM
OT  - Doxycycline
OT  - Mitochondrial translation
OT  - NLRP3 inflammasome
OT  - mtDNA
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/23 00:42
MHDA- 2023/12/22 06:42
CRDT- 2023/11/22 19:27
PHST- 2023/10/08 00:00 [received]
PHST- 2023/11/08 00:00 [revised]
PHST- 2023/11/16 00:00 [accepted]
PHST- 2023/12/22 06:42 [medline]
PHST- 2023/11/23 00:42 [pubmed]
PHST- 2023/11/22 19:27 [entrez]
AID - S0891-5849(23)01115-2 [pii]
AID - 10.1016/j.freeradbiomed.2023.11.014 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2024 Jan;210:75-84. doi: 
      10.1016/j.freeradbiomed.2023.11.014. Epub 2023 Nov 20.