Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes.
Animals
Antimicrobial Cationic Peptides
/ pharmacology
Biological Transport
/ drug effects
Cathelicidins
/ pharmacology
Cell Membrane
/ drug effects
Cholesterol
/ metabolism
Female
HEK293 Cells
Host-Pathogen Interactions
/ drug effects
Humans
Inflammation
/ pathology
Lipopolysaccharides
/ pharmacology
Mice, Inbred C57BL
Neutralization Tests
Polymyxin B
/ pharmacology
Signal Transduction
/ drug effects
antimicrobial peptides
endotoxin
hyperinflammation
immune regulation
membrane domains
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
entrez:
29
6
2021
pubmed:
30
6
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Antimicrobial peptides (AMPs) contribute to an effective protection against infections. The antibacterial function of AMPs depends on their interactions with microbial membranes and lipids, such as lipopolysaccharide (LPS; endotoxin). Hyperinflammation induced by endotoxin is a key factor in bacterial sepsis and many other human diseases. Here, we provide a comprehensive profile of peptide-mediated LPS neutralization by systematic analysis of the effects of a set of AMPs and the peptide antibiotic polymyxin B (PMB) on the physicochemistry of endotoxin, macrophage activation, and lethality in mice. Mechanistic studies revealed that the host defense peptide LL-32 and PMB each reduce LPS-mediated activation also via a direct interaction of the peptides with the host cell. As a biophysical basis, we demonstrate modifications of the structure of cholesterol-rich membrane domains and the association of glycosylphosphatidylinositol (GPI)-anchored proteins. Our discovery of a host cell-directed mechanism of immune control contributes an important aspect in the development and therapeutic use of AMPs.
Identifiants
pubmed: 34183393
pii: 2101721118
doi: 10.1073/pnas.2101721118
pmc: PMC8271772
pii:
doi:
Substances chimiques
Antimicrobial Cationic Peptides
0
Cathelicidins
0
Lipopolysaccharides
0
Cholesterol
97C5T2UQ7J
Polymyxin B
J2VZ07J96K
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
Competing interest statement: K.B. holds a patent for Aspidasept® and is the Chief Executive Officer of Brandenburg Antiinfectiva GmbH.
Références
J Immunol. 2004 Jun 15;172(12):7654-60
pubmed: 15187147
J Exp Med. 2001 Jul 2;194(1):79-88
pubmed: 11435474
Front Chem. 2019 Feb 04;7:43
pubmed: 30778385
J Exp Med. 1999 Jun 7;189(11):1777-82
pubmed: 10359581
J Immunol. 2011 Aug 15;187(4):1529-35
pubmed: 21810617
Antimicrob Agents Chemother. 2013 Mar;57(3):1480-7
pubmed: 23318793
Nat Rev Microbiol. 2012 Mar 16;10(4):243-54
pubmed: 22421877
Molecules. 2018 Feb 01;23(2):
pubmed: 29389911
Trends Immunol. 2014 Sep;35(9):443-50
pubmed: 25113635
J Immunol. 1999 Apr 1;162(7):3749-52
pubmed: 10201887
Nat Rev Immunol. 2003 Feb;3(2):169-76
pubmed: 12563300
J Immunol. 2009 Aug 15;183(4):2688-96
pubmed: 19605696
J Immunol. 1998 Nov 15;161(10):5464-71
pubmed: 9820522
J Cell Sci. 2004 Aug 1;117(Pt 17):4007-14
pubmed: 15286178
Science. 1990 Sep 21;249(4975):1429-31
pubmed: 2402637
Nat Immunol. 2019 May;20(5):527-533
pubmed: 30962589
Innate Immun. 2014 Nov;20(8):787-98
pubmed: 24122298
Science. 2020 May 1;368(6490):
pubmed: 32355003
Antimicrob Agents Chemother. 1998 Sep;42(9):2206-14
pubmed: 9736536
J Immunol. 2007 Dec 1;179(11):7684-91
pubmed: 18025214
Methods Mol Biol. 2007;398:59-72
pubmed: 18214374
Nat Rev Immunol. 2014 Aug;14(8):546-58
pubmed: 25060580
Crit Care. 2013 Nov 14;17(6):242
pubmed: 24229432
Curr Top Med Chem. 2017;17(5):508-519
pubmed: 28117020
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34
pubmed: 16330776
Nature. 2009 Apr 30;458(7242):1191-5
pubmed: 19252480
Chest. 2016 Feb;149(2):545-551
pubmed: 26502035
Nature. 2019 Dec;576(7787):452-458
pubmed: 31645764
Int Immunol. 2004 Jul;16(7):961-9
pubmed: 15184344
Nat Rev Immunol. 2017 Jul;17(7):407-420
pubmed: 28436424
Comb Chem High Throughput Screen. 2005 May;8(3):241-56
pubmed: 15892626
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4186-91
pubmed: 15010525
Biomacromolecules. 2016 Mar 14;17(3):862-73
pubmed: 26839947
Nat Chem Biol. 2013 Dec;9(12):761-8
pubmed: 24231617
Science. 1990 Sep 21;249(4975):1431-3
pubmed: 1698311
Biochim Biophys Acta. 2005 Sep 15;1715(2):122-31
pubmed: 16137644
Nature. 2002 Dec 19-26;420(6917):885-91
pubmed: 12490963
Eur J Biochem. 1969 Jun;9(2):245-9
pubmed: 5804498
Proc Natl Acad Sci U S A. 1979 Nov;76(11):5939-43
pubmed: 293694
J Immunol. 2012 Jul 1;189(1):304-11
pubmed: 22634613
J Biol Chem. 2010 Dec 31;285(53):41765-71
pubmed: 20966075
J Exp Med. 2000 Oct 2;192(7):1069-74
pubmed: 11015447
J Immunol. 2004 Mar 15;172(6):3758-65
pubmed: 15004180
Eur J Biochem. 1997 Jul 15;247(2):716-24
pubmed: 9266718
PLoS Pathog. 2019 Apr 12;15(4):e1007694
pubmed: 30978238
Nat Rev Immunol. 2016 May;16(5):321-34
pubmed: 27087664
Antimicrob Agents Chemother. 2010 Sep;54(9):3817-24
pubmed: 20606063
J Biol Chem. 2009 Nov 27;284(48):33255-64
pubmed: 19801678
Biopolymers. 2012;98(4):338-44
pubmed: 23193598
Nat Biotechnol. 2006 Dec;24(12):1551-7
pubmed: 17160061
J Immunol. 2006 Aug 1;177(3):1833-7
pubmed: 16849494
J Cell Sci. 2002 Jun 15;115(Pt 12):2603-11
pubmed: 12045230
Immunity. 2019 Jan 15;50(1):121-136.e5
pubmed: 30594464
Circ Res. 2009 Feb 27;104(4):455-65
pubmed: 19122179
Science. 1998 Dec 11;282(5396):2085-8
pubmed: 9851930
J Immunol. 2006 Feb 15;176(4):2455-64
pubmed: 16456005
J Endotoxin Res. 2006;12(5):261-77
pubmed: 17059690
J Biol Chem. 2009 Sep 11;284(37):25404-11
pubmed: 19592493