Theaflavin mitigates acute gouty peritonitis and septic organ injury in mice by suppressing NLRP3 inflammasome assembly.

Autor: Chen SY; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Li YP; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., You YP; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Zhang HR; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Shi ZJ; Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China., Liang QQ; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Yuan T; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Xu R; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Xu LH; Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Zha QB; Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. zhaqingbb@sina.com.; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China. zhaqingbb@sina.com., Ou-Yang DY; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. dongyun1967@aliyun.com., He XH; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. thexh@jnu.edu.cn.; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China. thexh@jnu.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2023 Oct; Vol. 44 (10), pp. 2019-2036. Date of Electronic Publication: 2023 May 23.
DOI: 10.1038/s41401-023-01105-7
Abstrakt: Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 μM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1β (IL-1β). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1β and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.
(© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: