title: Piperine metabolically regulates peritoneal resident macrophages to potentiate their functions against bacterial infection.
abstract: Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection.
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Huang
authors.affiliation: Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Qing-Bing
authors.initials: QB
authors.lastname: Zha
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Gao-Xiang
authors.initials: GX
authors.lastname: Zhao
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Hou
authors.affiliation: Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Zi-Jian
authors.initials: ZJ
authors.lastname: Shi
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Qiu-Ru
authors.initials: QR
authors.lastname: Lin
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Ouyang
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000596:Amino Acids; D000900:Anti-Bacterial Agents; D052117:Benzodioxoles; D027282:Fusion Regulatory Protein 1, Heavy Chain; D018836:Inflammation Mediators; D015850:Interleukin-6; D027283:Large Neutral Amino Acid-Transporter 1; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; C523212:Slc3A2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C008922:piperine
keywords: Immune response; Immunity; Immunology and Microbiology Section; SLC7A5/SLC3A2; bacterial infection; mTORC1; peritoneal macrophages; piperine