title: Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities.
abstract: Bacterial colonization of the lower respiratory tract is frequently seen in chronic obstructive pulmonary disease (COPD), and may cause exacerbations leading to disease progression. Antimicrobial peptides comprise an important part of innate lung immunity, and not least the cathelicidin human cationic antimicrobial protein-18/LL-37. Peptidylarginine deiminases (PADIs) post-translationally modify proteins by converting cationic peptidylarginine residues to neutral peptidylcitrulline. An increased presence of PADI2 and citrullinated proteins was demonstrated in the lungs of smokers. In this study, preformed PADI4, stored in granulocytes and extracellularly in the lumina of bronchi, was found in lung tissue of individuals suffering from COPD. In vitro, recombinant human PADI2 and PADI4 both caused a time- and dose-dependent citrullination of LL-37. The citrullination resulted in impaired antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, and nontypable Haemophilus influenzae, but less so against Pseudomonas aeruginosa. Using artificial lipid bilayers, we observed discrete differences when comparing the disrupting activity of native and citrullinated LL-37, suggesting that differences in cell wall composition are important during interactions with whole bacteria. Furthermore, citrullinated LL-37 showed higher chemotactic activity against mononuclear leukocytes than did native LL-37, but was less efficient at neutralizing lipolysaccharide, and also in converting apoptotic neutrophils into a state of secondary necrosis. In addition, citrullinated LL-37 was more prone to degradation by proteases, whereas the V8 endopetidase of S. aureus cleaved the modified peptide at additional sites, compared with native LL-37. Together, these findings demonstrate novel mechanisms whereby the inflammation-dependent deiminases PADI2 and PADI4 can alter the activites of antibacterial polypeptides, affecting the course of inflammatory disorders such as COPD.
authors.affiliation: Section for Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University and Skåne University Hospital, BMC B14, Tornavägen 10, Lund, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Kilsgård
authors.forename: Pia
authors.initials: P
authors.lastname: Andersson
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Sara L
authors.initials: SL
authors.lastname: Nordin
authors.forename: Helena M
authors.initials: HM
authors.lastname: Linge
authors.forename: Mette
authors.initials: M
authors.lastname: Eliasson
authors.forename: Eva
authors.initials: E
authors.lastname: Sörenson
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Erjefält
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Ole E
authors.initials: OE
authors.lastname: Sørensen
authors.forename: Arne
authors.initials: A
authors.lastname: Egesten
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000502:physiology*; D001980:Bronchi / Q000201:enzymology*; D002942:Circular Dichroism; D002956:Citrulline / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006193:Haemophilus influenzae / Q000502:physiology; D006867:Hydrolases / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology*; D013058:Mass Spectrometry; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D059748:Proteolysis; D011550:Pseudomonas aeruginosa / Q000502:physiology; D012907:Smoking; D013211:Staphylococcus aureus / Q000502:physiology; D013296:Streptococcus pneumoniae / Q000502:physiology; D014132:Trachea / Q000201:enzymology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D002956:Citrulline; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D054804:Cathelicidins