An Antimicrobial Cathelicidin Peptide, Human CAP18/LL-37, Suppresses Neutrophil Apoptosis via the Activation of Formyl-Peptide Receptor-Like 1 and P2X7

Abstract

Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. An antibacterial cathelicidin, human cationic antibacterial protein of 18 kDa/LL-37, not only exhibits potent bactericidal activities against Gram-negative and Gram-positive bacteria, but also functions as a chemoattractant for immune cells, including neutrophils. During bacterial infections, the life span of neutrophils is regulated by various pathogen- and host-derived substances. In this study, to further evaluate the role of LL-37 in innate immunity, we investigated the action of LL-37 on neutrophil apoptosis. Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, LL-37 dose dependently (0.01–5 μg/ml) suppressed neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/2, expression of Bcl-xL (an antiapoptotic protein), and inhibition of caspase 3 activity. Interestingly, LL-37-induced suppression of neutrophil apoptosis was attenuated by the antagonists for formyl-peptide receptor-like 1 (FPRL1) and P2X7 nucleotide receptor. Of importance, the agonists for FPRL1 and P2X7 apparently suppressed neutrophil apoptosis. Collectively, these observations indicate that LL-37 cannot only kill bacteria, but also modulate (suppress) neutrophil apoptosis via the activation of FPRL1 and P2X7 in bacterial infections. Suppression of neutrophil apoptosis results in the prolongation of their life span, and may be advantageous for host defense against bacterial invasion.

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…5A). Previously, G i -coupled receptors have been shown to mediate some of the effects of human cathelicidin LL-37 on leukocytes, with formyl peptide receptor-like 1 (FPRL-1) being one of the receptors involved (7,8,10,11). Therefore, we further analyzed the effects of an FPRL-1 antagonist WRW4 on the activity of peptide IDR-1002.…”

“…The microbicidal activity of peptides is due to their preferential interactions with prokaryotic membranes, leading to bacterial membrane disruption and/or targeting of intracellular bacterial molecules (5,6). The immunomodulatory activities of such peptides are extremely diverse and include stimulation of chemotaxis and chemokine production (7,8), promotion of leukocyte antimicrobial functions (9), regulation of neutrophil and epithelial cell apoptosis (10,11), regulation of dendritic cell differentiation and activation, stimulation of epithelial cell migration and wound healing, promotion of angiogenesis, and many others (reviewed in Refs. 12,13).…”

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

“…LL-37 is found in the secondary granules of neutrophils (7), is endogenously expressed by a variety of cells including keratinocytes and epithelial cells, and is released in response to multiple inflammatory stimuli (8,9). On release, LL-37 acts as an effector molecule of innate immunity, displaying anti-infective and immunomodulatory activities, including the induction of neutrophil, CD4 + T-cell and monocyte chemotaxis (10), mast cell activation (11), and neutrophil survival (12,13). However, a concentration of 100 μg/mL of LL-37 resulted in the death of 60% untransformed human airway epithelial cells (14).…”

Gene expression profile of type II spinal cord decompression sickness

“…Of these 17 genes, the 18-kDa cationic antimicrobial protein, macrophage migration inhibitory factor, defensin-4, interleukin-12A, interferon-aA and neutrophil sterilization protein are involved in inflammation, immune response and stress. [14][15][16][17] The leucine-rich repeat (LRR) family member LRRC48 was obviously downregulated. The LRR protein is widely distributed in eukaryotic and prokaryotic cells and tissues.…”