Abstract
Protegrins are porcine antimicrobial peptides (AMPs) that belong to the cathelicidin family of host defense peptides. Protegrin-1 (PG-1), the most investigated member of the protegrin family, is an arginine-rich peptide consisting of 18 amino acid residues, its main chain adopting a β-hairpin structure that is linked by two disulfide bridges. We report on the immune modulatory activity of PG-1 and its analogs in neutralizing bacterial endotoxin and capsular polysaccharides, consequently inhibiting inflammatory mediators’ release from macrophages. We demonstrate that the β-hairpin structure motif stabilized with at least one disulfide bridge is a prerequisite for the immune modulatory activity of this type of AMP.
Highlights
The innate immune system protects the host by rapid detection and elimination of invading pathogens.Phagocytic cells are equipped with pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) [1], scavenger receptors, and others that facilitate rapid detection of invading pathogens [2,3].Phagocytes are equipped with bactericidal compounds like lysozymes and host defense cationic peptides that facilitate rapid killing of pathogens [4,5,6]
PG-1, as a cationic peptide, has the ability to bind to anionic components of bacterial membranes; this includes LPS and capsular polysaccharide (CPS) polymers which act as Toll-like receptor (TLR) ligands and function as potent inducers of inflammatory responses in macrophages [56,57]
We previously reported that porcine cathelicidin, PG-1, inhibits meningococcal LOS immune stimulatory activity and reduces TNFα and nitric oxide release from human and murine macrophages, respectively [22], indicating that a similar mechanism applies to this beta-forming peptide
Summary
The innate immune system protects the host by rapid detection and elimination of invading pathogens. PG-1, as a cationic peptide, has the ability to bind to anionic components of bacterial membranes; this includes LPS and capsular polysaccharide (CPS) polymers which act as Toll-like receptor (TLR) ligands and function as potent inducers of inflammatory responses in macrophages [56,57]. In this study we investigated the immune modulatory activity of PG-1 and several of its analogs and evaluated the importance of disulfide bridges as well as hydrogen bonding potential of its main chain on the ability to neutralize TLR ligand bioactivity in macrophages, dampening inflammatory mediators’ release. We report that synthetic PG-1 analogs adopting (and maintaining) the β-hairpin fold bearing at least one disulfide bridge exert potent immune modulatory activity against meningococcal.
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