title: Identifying the Critical Domain of LL-37 Involved in Mediating Neutrophil Activation in the Presence of Influenza Virus: Functional and Structural Analysis.
abstract: The human cathelicidin LL-37 has been shown to play a role in host defense against influenza A viruses (IAV) through direct antiviral effects and through modulating inflammatory responses to infection. We recently showed that LL-37 increases neutrophil respiratory burst and neutrophil extracellular trap (NET) responses to IAV through engaging formyl peptide receptor 2 (FPR-2). In this paper we show that a fragment of LL-37, GI-20, which is composed of the central helical segment of the peptide, has similar effects as LL-37 on neutrophil activation. In addition to increasing respiratory burst and NET responses of the cells to IAV through an FPR-2 dependent mechanism, it reduces neutrophil IL-8 production to IAV (also like LL-37). The N-terminal fragment, LL-23, did not have similar effects. Both GI-20 and LL-37 increase neutrophil intracellular calcium levels and their ability to increase neutrophil activation responses was calcium dependent and partially inhibited by pertussis toxin. These studies show that the central helix of LL-37 retains the ability of LL-37 to modulate neutrophil responses through FPR-2. Based on our findings we developed a homology model of FPR-2 and performed docking experiments of LL-37 and GI-20 with the receptor.
authors: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors: Shweta
authors: S
authors: Tripathi
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America.
authors: Guangshun
authors: G
authors: Wang
authors: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors: Mitchell
authors: M
authors: White
authors: Boston University School of Medicine, Department of Biophysics, Boston, MA, United States of America.
authors: Michael
authors: M
authors: Rynkiewicz
authors: Boston University School of Medicine, Department of Biophysics, Boston, MA, United States of America.
authors: Barbara
authors: B
authors: Seaton
authors: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors: Kevan
authors: K
authors: Hartshorn
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D065206:Extracellular Traps / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C105101:FPR2 protein, human; D016209:Interleukin-8; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D054804:Cathelicidins