title: Reduction Impairs the Antibacterial Activity but Benefits the LPS Neutralization Ability of Human Enteric Defensin 5.
abstract: Oxidized human defensin 5 (HD5OX), a Paneth cell-secreted antibacterial peptide with three characteristic disulfide bonds, protects the host from invasion by morbigenous microbes in the small intestine. HD5OX can be reduced by thioredoxin (Trx) in vitro, while the biochemical properties of the reduced linear peptide, HD5RED, remain unclear. Here, we first confirm that HD5RED does exist in vivo. Furthermore, we reveal that the recruitment of HD5RED to the outer membrane of Gram-negative bacteria and to the anionic lipid A is lower than that of HD5OX, and HD5RED is less efficient in penetrating bacterial outer and inner membranes and inducing membrane depolarization, which confers an attenuated antibacterial activity to HD5RED. However, due to its higher structural flexibility, the binding of HD5RED to bacterial lipopolysaccharide (LPS) is markedly stronger than that of HD5OX. Consequently, HD5RED is more effective in suppressing the production of the pro-inflammatory cytokine TNF-α in LPS-stimulated macrophages by blocking the interaction between LPS and LPS-binding protein, thus suggesting that HD5RED might act as a scavenger to neutralize LPS in the gut. This study provides insights into the antibacterial and immunoregulatory effects of HD5RED and expands the known repertoire of the enteric defensins.
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Naixin
authors.initials: N
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.|Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Su
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Tianmin
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Wang
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001826:Body Fluids / Q000737:chemistry; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011485:Protein Binding; D012486:Salmonella typhimurium / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023084:alpha-Defensins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D023084:alpha-Defensins; D000099231:Lipopolysaccharide-Binding Protein