Bergenin is a natural PPARy agonist that can prevent neutrophil aggregation,and often be used in clinics for treating respiratory diseases.Recent data show that Th17 cells are important for neutrophil aggregation and asthma through secreting IL-17A.In this study,we investigated the effects of bergenin on Th17 differentiation in vitro and subsequent neutrophilic asthma in mice.Naive T cells isolated from mouse mesenteric lymph nodes were treated with IL-23,TGF-β,and IL-6 to induce Th17 differentiation.We showed that in naive T cells under Th17-polarizing condition,the addition of bergenin(3,10,30 μM)concentration-dependently decreased the percentage of CD4+IL-17A+T cells and mRNA expression of specific transcription factor RORyt,and function-related factors IL-17A/F,IL-21,and IL-22,but did not affect the cell vitality and apoptosis.Furthermore,bergenin treatment prevented GLS1-dependent glutaminolysis in the progress of Th17 differentiation,slightly affected the levels of SLC1A5,SLC38A1,GLUD1,GOT1,and GPT2.Glutamine deprivation,the addition of glutamate(1 mM),α-ketoglutarate(1 mM),or GLS1 plasmid all significantly attenuated the above-mentioned actions of bergenin.Besides,we demonstrated that bergenin(3,10,and 30 μM)concentration-dependently activated PPARy in naive T cells,whereas PPARy antagonist GW9662 and siPPARy abolished bergenin-caused inhibition on glutaminolysis and Th17 differentiation.Furthermore,we revealed that bergenin inhibited glutaminolysis by regulating the level of CDK1,phosphorylation and degradation of Cdh1,and APC/C-Cdh1-mediated ubiquitin-proteasomal degradation of GLS1 after activating PPARy.We demonstrated a correlation existing among bergenin-affected GLS1-dependent glutaminolysis,PPARγ,"CDK1-APC/C-Cdh1"signaling,and Th17 differentiation.Finally,the therapeutic effect and mechanisms for bergenin-inhibited Th17 responses and neutrophilic asthma were confirmed in a mouse model of neutrophilic asthma by administration of GW9662 or GLS1 overexpression plasmid in vivo.In conclusion,bergenin repressed Th17 differentiation and then alleviated neutrophilic asthma in mice by inhibiting GLS1-dependent glutaminolysis via regulating the"CDK1-APC/C-Cdh1"signaling after activating PPARγ.

Ling Yang;Yun Zheng;Yu-meng Miao;Wen-xin Yan;Yan-zhi Geng;Yue Dai;Zhi-feng Wei

Department of Pharmacology of Chinese Materia Medica,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 210009,China

中国药理学报（英文版）

[1]Ling Yang;Yun Zheng;Yu-meng Miao;Wen-xin Yan;Yan-zhi Geng;Yue Dai;Zhi-feng Wei-.Bergenin,a PPARγ agonist,inhibits Th17 differentiation and subsequent neutrophilic asthma by preventing GLS1-dependent glutaminolysis)[J].中国药理学报（英文版）,2022(04):963-976

Bergenin,bergenin,17A+T,RORyt,SLC38A1,siPPARy

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