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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (4) : 594-607    https://doi.org/10.1007/s11684-020-0809-2
RESEARCH ARTICLE
Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity
Nan Qin1,2, Guang Xu1, Yan Wang1,3, Xiaoyan Zhan1, Yuan Gao4, Zhilei Wang1, Shubin Fu1, Wei Shi1, Xiaorong Hou1, Chunyu Wang1, Ruisheng Li5, Yan Liu5, Jiabo Wang1, Haiping Zhao6(), Xiaohe Xiao1,7(), Zhaofang Bai1()
1. China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
2. Department of Pharmacy, Nantong Hospital of Traditional Chinese Medicine, Nantong 226300, China
3. School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
4. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
5. Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
6. School of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
7. Integrative Medical Centre, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
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Abstract

Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

Keywords Psoraleae Fructus      bavachin      idiosyncratic drug-induced liver injury      caspase-1      IL-1β      NLRP3 inflammasome     
Corresponding Author(s): Haiping Zhao,Xiaohe Xiao,Zhaofang Bai   
Just Accepted Date: 03 December 2020   Online First Date: 27 April 2021    Issue Date: 23 September 2021
 Cite this article:   
Nan Qin,Guang Xu,Yan Wang, et al. Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity[J]. Front. Med., 2021, 15(4): 594-607.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0809-2
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I4/594
Fig.1  NLRP3 inflammasome activation on main ingredients isolated from Psoralea corylifolia L. (A) Activity of caspase-1 in culture supernatants (Sup.) from LPS-primed BMDMs treated with MSU (200 µg/mL) or eight ingredients (10 µmol/L) from PL for 24 h. (B) Activity of caspase-1 in the Sup. from LPS-primed BMDMs treated with eight ingredients (10 µmol/L) from PL for 1 h and then stimulated by ATP for 1 h. (C) Bavachin structure. (D) Cytotoxicity in BMDMs treated with bavachin (2.5, 5, 10, 20, 40, 60, 80, 120, and 160 µmol/L). Data are expressed as the mean±SEM of at least three independent experiments. ###P<0.001 vs. the control group. *P<0.05, **P<0.01, ***P<0.001 vs. the LPS plus ATP group.
Fig.2  Bavachin promotes the activation of the NLRP3 inflammasome triggered by ATP or nigericin. (A) LPS-primed BMDMs were treated with various doses of bavachin (2.5, 5, and 10 µmol/L) and then stimulated with ATP. Western blot analysis of IL-1β (p17) and caspase-1 (Casp-1 p20) in culture supernatants (Sup.) and pro-IL-1β, caspase-1 (Casp-1 p45), NLRP3, and ASC in cell lysates (Lys.). (B, C) Activity of caspase-1(B) and production of IL-1b (C) in the Sup. from BMDMs described in (A). (D) LPS-primed BMDMs were stimulated with nigericin after being treated with different concentrations (2.5, 5, and 10 µmol/L) of bavachin. Western blot analysis of IL-1β (p17) and caspase-1 (Casp-1 p20) in the Sup. and pro-IL-1β, caspase-1 (Casp-1 p45), NLRP3, and ASC in cell Lys. (E, F) Activity of caspase-1 (E) and production of IL-1b (F) in the Sup. from BMDMs described in (D). (G) TNF-α in the Sup. from BMDMs described in (A). (H) TNF-α in the Sup. from BMDMs described in (D). Coomassie blue staining was provided as the loading control for the Sup. (A and D). GAPDH was provided as the loading control for Lys. (A and D). Data are expressed as the mean±SEM of at least three independent experiments. ###P<0.001 vs. the control group. **P<0.01, ***P<0.001 vs. the LPS plus ATP or nigericin group. ns, not significant.
Fig.3  Bavachin has no effect on other stimuli-induced NLRP3 inflammasome activation and NLRC4, AIM2 inflammasome activation. (A) Western blot analysis of IL-1β (p17) and caspase-1 (Casp-1 p20) in culture supernatants (Sup.) and pro-IL-1β, caspase-1 (Casp-1 p45), NLRP3, and ASC in cell lysates (Lys.) from LPS-primed BMDMs treated with bavachin (10 µmol/L) or not and then stimulated with ATP, nigericin, MSU, and poly(I:C). (B) Western blot analysis of IL-1b (p17), caspase-1 (Casp-1 p20) in the Sup. and pro-IL-1β, caspase-1 (Casp-1 p45), NLRP3, and ASC in cell Lys. from LPS-primed BMDMs treated in the presence or absence of bavachin (10 µmol/L) and then stimulated with nigericin, poly(dA:dT), Salmonella, or Pam3CSK4-primed BMDMs treated with bavachin (10 µmol/L) and then transfected with LPS (1 µg/mL). (C–E) Activity of caspase-1 (C), production of IL-1b (D) and TNF-a (E) in the Sup. from BMDMs described in (A). (F–H) Activity of caspase-1 (F), release of IL-1b (G), and TNF-a (H) in the Sup. from BMDMs described in (B). Coomassie blue staining was provided as the loading control for the Sup. (A and B). GAPDH was provided as the loading control for the Lys. (A and B). Data are expressed as the mean±SEM of at least three independent experiments. *P<0.05, ***P<0.001. ns, not significant.
Fig.4  Bavachin facilitates ASC oligomerization. (A) Western blots analysis of cell lysates and cross-linked cytosolic pellets of LPS-primed BMDMs stimulated with bavachin (10 µmol/L) and then stimulated with ATP, nigericin, and MSU. (B) Western blots analysis of cell lysates and cross-linked cytosolic pellets of LPS-primed BMDMs treated with bavachin (10 µmol/L) before stimulating nigericin, poly(dA:dT), Salmonella, or Pam3CSK4-primed BMDMs treated with bavachin (10 µmol/L) and then transfection with LPS. GAPDH served as a loading control for the Lys.
Fig.5  Bavachin does not affect the LPS-induced NLRP3 priming, K+ efflux but specifically promotes nigericin-induced mitochondrial ROS production. (A) Western blot analysis of pro-IL-1β and NLRP3 in cell lysates from BMDMs treated with different doses of bavachin (2.5, 5, 10 µmol/L) for 1 h and then stimulated with LPS for 4 h. (B) Production of TNF-α (as measured by ELISA) in culture supernatants from BMDMs described in (A). (C) Immunofluorescence analysis in LPS-primed BMDMs treated with bavachin (10 µmol/L) and then left stimulated with nigericin, followed by staining with Mitotracker red and DAPI. (D) Relative level of intracellular K+ determined by inductively coupled plasma optical emission spectrometry in LPS-primed BMDMs and stimulated with ATP at different times. (E, F) LPS-primed BMDMs were treated with bavachin (5 and 10 µmol/L) and then stimulated with nigericin or SiO2. BMDMs were loaded with MitoSOX red mitochondrial superoxide indicator (Ex/Em: 510/580 nm) (E). After staining and washing, flow cytometry was conducted to test mtROS production (F). Data are expressed as the mean±SEM of at least three independent experiments. ###P<0.001 vs. the control, ***P<0.001 vs. LPS plus nigericin. ns, not significant.
Fig.6  Bavachin induces liver injury in LPS-mediated IDILI mouse model. Female C57BL/6 mice were treated with LPS (2 mg/kg) or its saline vehicle through the tail vein. After 2 h, bavachin (25 mg/kg) or its vehicle was administered through intraperitoneal injection. Mice were sacrificed 6 h later (n = 6 animals per group). (A) Serum ALT activity, (B) AST activity, (C) IL-1β, and (D) TNF-α were measured using their assay kits. Data are expressed as mean±SEM. #P<0.05, ##P<0.01 vs. the control; ***P<0.001 vs. LPS alone.
Fig.7  MCC950 pretreatment suppresses liver injury induced by LPS/bavachin. Female C57BL/6 mice were given MCC950 (50 mg/kg) or its vehicle through intraperitoneal injection for 1 h. Then, female C57BL/6 mice received LPS (2 mg/kg) or its saline vehicle, intravenous injection via a tail vein. After 2 h, bavachin (25 mg/kg) or its vehicle was treated by intraperitoneal injection. After 6 h of bavachin administration (n = 6 animals per group), the serum levels of ALT (A), AST(B), IL-1β (C), and TNF-α (D) were measured using their assay kits. Data are expressed as mean±SEM. *P<0.05, **P<0.01, ***P<0.001.
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