Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells

Abstract

We have previously shown that antimicrobial peptides like defensins have the capacity to mobilize leukocytes in host defense. LL-37 is the cleaved antimicrobial 37-residue, COOH-terminal peptide of hCAP18 (human cationic antimicrobial protein with a molecular size of 18 kD), the only identified member in humans of a family of proteins called cathelicidins. LL-37/hCAP18 is produced by neutrophils and various epithelial cells. Here we report that LL-37 is chemotactic for, and can induce Ca2+ mobilization in, human monocytes and formyl peptide receptor–like 1 (FPRL1)-transfected human embryonic kidney 293 cells. LL-37–induced Ca2+ mobilization in monocytes can also be cross-desensitized by an FPRL1-specific agonist. Furthermore, LL-37 is also chemotactic for human neutrophils and T lymphocytes that are known to express FPRL1. Our results suggest that, in addition to its microbicidal activity, LL-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and T cells to sites of microbial invasion by interacting with FPRL1.

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.…”

“…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. 5,10 Thus, the marked hCAP18/LL-37 expression in breast cancer cells presented herein may reflect a growth advantage for these tumor cells.…”

“…The G-protein-coupled receptor FPRL1 has been shown to mediate LL-37-induced effects in eukaryote cells; 4,5 to assess its potential role in the present setting, we investigated the expression of FPRL1 protein in mammary tissue and found strong immunoreactivity for FPRL1 both in breast cancer cells and in normal glandular epithelium (Fig. 5a and b).…”

“…1,2 Extracellular proteolytic processing of the holoprotein releases the LL-37 peptide, which has broad antimicrobial activity 1,3 as well as effects on host cells mediated by the G-protein-coupled receptor, formyl peptide receptor-like 1 (FPRL1). 4,5 hCAP18 is present in leucocytes 6 and is expressed in skin and other epithelia, where it is upregulated in association with inflammation 7,8 and injury, 9,10 consistent with a role in innate barrier protection. Recently, antimicrobial proteins including cathelicidins have been proposed to play a role also in the nonspecific host defense against tumors.…”

How dying cells alert the immune system to danger

“…These include HSPs 47, 48 49 50, S100 proteins 51,52 , nucleosomes 53,54 , purines such as ATP and adenosine 55,56 , antimicrobial peptides 57,58 59 and N-formylated mitochondrial peptides 60 . The contribution of these molecules to death-induced inflammation in vivo is also unknown.…”