The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock.
Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1βand IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1β, IL-18, andNlrp3in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1βand IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock.
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Xiaoli
0000-0003-3513-3551
X
Chen
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Ning
0000-0002-9913-5006
N
Wang
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Yuanfeng
0000-0002-6414-6709
Y
Zhu
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Yongling
0000-0003-0092-7036
Y
Lu
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Xin
0000-0002-2986-6364
X
Liu
Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Jiang
0000-0002-9049-2234
J
Zheng
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D002738:Chloroquine