A cathelicidin family of human antibacterial peptide LL‐37 induces mast cell chemotaxis

Abstract

SUMMARYThe mast cell is one of the major effector cells in inflammatory reactions and can be found in most tissues throughout the body. During inflammation, an increase in the number of mast cells in the local milieu occurs, and such accumulation requires directed migration of this cell population. As it has previously been reported that the human cathelicidin-derived antibacterial peptide, LL-37, stimulates the degranulation of mast cells, we hypothesized that LL-37 could be a mast cell chemotaxin. The present study shows that LL-37 is a potent chemotactic factor for mast cells. The chemotactic response was dose-dependent and bellshaped, reaching an optimal concentration of 5 mg/ml. In addition, checkerboard analysis showed that cell migration towards this peptide was chemotactic rather than chemokinetic. Moreover, Scatchard analysis using 125 I-labelled LL-37-derived peptide revealed that LL-37 has at least two classes of receptors, namely high-and low-affinity receptors, on mast cells. Furthermore, the competitive binding assay suggested that LL-37 is unlikely to utilize formyl peptide receptor-like 1 (FPRL1), a functional LL-37 receptor for neutrophil and monocyte migration, on mast cells. In addition, the treatment of cells with pertussis toxin and phospholipase C inhibitor, U-73122, inhibited LL-37-mediated migration, indicating that LL-37 induces mast cell chemotaxis through a Gi protein-phospholipase C signalling pathway. These results show that besides its antibacterial activities, LL-37 may have the potential to recruit mast cells to inflammation foci.

Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator

“…It has become increasingly clear that some antimicrobial peptides, exemplified by defensins, function in local innate immunity not only as lytic agents but also as modifiers of immune cell migration and activation, further promoting their protective effects (7)(8)(9)(10). We show in this study that granulysin not only contributes to innate immunity but also to adaptive immunity as it attracts and activates human monocytes, dendritic, NK, and T cells.…”

“…Human ␤ defensin 3 also is chemotactic for monocytes, cells that do not express CCR6, suggesting the presence of additional receptors. Cathelicidin (LL37) is broadly chemoattractant for monocytes, neutrophils, and T cells but not iDC (8,10,25). Its receptor is the formyl peptide receptor-like 1, another G-proteincoupled receptor (28).…”

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

“…In addition to pathogen inactivation through a direct membrane effect, LL-37 exerts chemotactic effects in vitro, inducing migration of human neutrophils, monocytes, subsets of T-cells and mast cells. 4,35,36 This chemotactic activity is dependent on binding of LL-37 to FPRL1, a pertussis toxin-sensitive membrane-bound G-protein-coupled receptor. 4 Additional suggested functions for hCAP18/LL-37 include a role in epithelial repair and angiogenesis by promoting reepithelialization of skin wounds and neovascularization.…”

Cathelicidins in inflammation and tissue repair: Potential therapeutic applications for gastrointestinal disorders

“…To date, cathelicidins from four different mammals including bovine [13] , porcine [7] , human [2,8,14] , and mice [15] have been reported to function as leukocyte chemoattractants. They chemoattract neutrophils, monocytes, mast cells, and T-cells to inflammatory sites at sub-antimicrobial concentrations [7] .…”