The Human Antimicrobial Peptide LL-37 Is a Multifunctional Modulator of Innate Immune Responses

Abstract

The role of LL-37, a human cationic antimicrobial peptide, in the immune system is not yet clearly understood. It is a widely expressed peptide that can be up-regulated during an immune response. In this report, we demonstrate that LL-37 is a potent antisepsis agent with the ability to inhibit macrophage stimulation by bacterial components such as LPS, lipoteichoic acid, and noncapped lipoarabinomannan. We also demonstrate that LL-37 protects mice against lethal endotoxemia. In addition to preventing macrophage activation by bacterial components, we hypothesized the LL-37 may also have direct effects on macrophage function. We therefore used gene expression profiling to identify macrophage functions that might be modulated by LL-37. These studies revealed that LL-37 directly up-regulates 29 genes and down-regulated another 20 genes. Among the genes predicted to be up-regulated by LL-37 were those encoding chemokines and chemokine receptors. Consistent with this, LL-37 up-regulated the expression of chemokines in macrophages and the mouse lung (monocyte chemoattractant protein 1), human A549 epithelial cells (IL-8), and whole human blood (monocyte chemoattractant protein 1 and IL-8), without stimulating the proinflammatory cytokine, TNFα. LL-37 also up-regulated the chemokine receptors CXCR-4, CCR2, and IL-8RB. These findings indicate that LL-37 may contribute to the immune response by limiting the damage caused by bacterial products and by recruiting immune cells to the site of infection so that they can clear the infection.

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

“…LL-37 induces chemokine secretion in airway epithelial cell lines, human whole blood, and mouse models (13,36,37). In this study we demonstrated that the activation of ERK1/2 and p38 kinases is required for LL-37-induced transcription of the chemokines IL-8, MCP-1, and MCP-3 in human blood-derived monocytes.…”

“…We have recently demonstrated that LL-37 induced the secretion of chemokines in the human A549 epithelial cell line (IL-8) and whole human blood (MCP-1 and IL-8) (13). In addition to testing for LDH levels, the supernatants from human blood-derived monocytes treated with 10 -200 g/ml, the cytotoxic peptide CP29 (50 g/ml), or a vehicle control for up to 4 h were assayed for IL-8 secretion by ELISA.…”

“…LL-37 is a potent modulator of the immune response, and to date a wide variety of interactions with the effector cells of the immune response have been described (11). Monocytes, the precursors of both macrophages and certain lineages of dendritic cells, have been shown to demonstrate chemotaxis toward LL-37 (12), which is also able to stimulate the production of chemokines and chemokine receptors (13). A variety of cationic peptides can also reduce proinflammatory cytokine production by macrophages to Toll-like receptor agonists, such as LPS (14).…”

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

“…LL-37 selectively reduces proinflammatory macrophage responses (Brown et al, 2011) and inhibits dsRNA/TLR3-induced TNF-␣ and IL-8 in keratinocytes (Chen et al, 2013). Consistent with these suppressive effects in vitro, LL-37 is protective in mouse models of LPS-induced sepsis (Scott et al, 2002). In addition, LL-37 up-regulates formyl peptide receptor-like 1 (FPRL1) expression (Carretero et al, 2008) and inhibits apoptosis by activating the cyclooxygenase 2 (COX-2) pathway in HaCaT cells (Chamorro et al, 2008).…”

Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities

“…LL-37 has also been shown to stimulate host inflammatory events (21,24). The skin has demonstrated dependence on cathelicidin expression for resistance to infection by Streptococcus pyogenes in mice (25), and cathelicidin expression correlates with resistance to human skin infections (26).…”