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Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis

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Acta Pharmaceutica Sinica B 2022年第1期12卷 228-245页

作者： Heng Li Yao Zhang Moting Liu Chen Fan Chunlan Feng Qiukai Lu caigui xiang Huimin Lu Xiaoqian Yang Bing Wu Duowu Zou Wei Tang Laboratory of Anti-inflammation and Immunopharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmacy University of Chinese Academy of SciencesBeijing 100049China Department of Gastroenterology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Phosphodiesterase-4(PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate(c AMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis(UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors,to explore the therapeutic capacity in dextran sulfate sodium(DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective c AMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated c AMP-predominant protein kinase A(PKA)-c AMP-response element binding protein(CREB)signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present studyrevealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.

关键词： Ulcerative colitis PDE4 Mucosal homeostasis Gut microbiota Epithelial barrier

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Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions

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Acta Pharmaceutica Sinica B 2020年第3期10卷 447-461页

作者： Heng Li Chen Fan Huimin Lu Chunlan Feng Peilan He Xiaoqian Yang caigui xiang Jianping Zuo Wei Tang Laboratory of Anti-inflammation and Immunopharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmacy University of Chinese Academy of SciencesBeijing 100049China Laboratory of Immunology and Virology Shanghai University of Traditional Chinese MedicineShanghai 201203China

Ulcerative colitis(UC)manifests as an etiologically complicated and relapsing gastrointestinal disease.The enteric nervous system(ENS)plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract.Berberine,an isoquinoline alkaloid,is known as its antiinflammatory and therapeutic effects in experimental colitis.However,little research focused on its regulatory function on ENS.Therefore,we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro-immune interactions.Functional defects of enteric glial cells(EGCs),with decreased glial fibrillary acidic protein(GFAP)and increased substance P expression,were observed in DSS-induced murine UC.Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC,closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation.In vitro,berberine showed direct protective effects on monoculture of EGCs,bone marrowderived dendritic cells(BMDCs),T cells,and intestinal epithelial cells(IECs)in the simulated inflammatory conditions.Furthermore,berberine could modulate gut EGCs-IECs-immune cell interactions in the co-culture systems.In summary,our study indicated the EGCs-IECs-immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.

关键词： Ulcerative colitis Berberine Mucosal inflammation Enteric glial cells Enteric nervous system

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