Modulation of host defense peptide-mediated human mast cell activation by LPS.
Human β-defensin3 (hBD3) and the cathelicidin LL-37 are host defense peptides (HDPs) that directly kill microbes and display immunomodulatory/wound-healing properties via the activation of chemokine, formylpeptide and epidermal growth factor receptors on leukocytes and epithelial cells. A C-terminal 14 amino acid hBD3 peptide with all Cys residues replaced with Ser (CHRG01) and an LL-37 peptide consisting of residues 17-29 (FK-13) display antimicrobial activity but lack immunomodulatory property. Surprisingly, we found that CHRG01 and FK-13 caused Ca(2+) mobilization and degranulation in human mast cells via a novel G protein-coupled receptor known as Mas-related gene-X2 (MrgX2). At local sites of bacterial infection, the negatively charged LPS likely interacts with cationic HDPs to inhibit their activity and thus providing a mechanism for pathogens to escape host defense mechanisms. We found that LPS caused almost complete inhibition of hBD3 and LL-37-induced Ca(2+) mobilization and mast cell degranulation. In contrast, it had no effect on CHRG01 and FK-13-induced mast cell responses. These findings suggest that HDP derivatives that kill microbes, harness mast cell's host defense and wound-healing properties via the activation of MrgX2 but are resistant to inhibition by LPS could be utilized for the treatment of antibiotic-resistant microbial infections.
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
Kshitij
K
Gupta
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
Hariharan
H
Subramanian
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA alih@upenn.edu.
Hydar
H
Ali
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D008070:Lipopolysaccharides / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; C422950:DEFB103A protein, human; D008070:Lipopolysaccharides; C480039:MRGPRX2 protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D023083:beta-Defensins; D054804:Cathelicidins
Host defense peptides; LPS; Mas-related gene-X2 (MrgX2); mast cell