Impact of LL-37 on anti-infective immunity

Abstract

Host defense peptides (often called cationic antimicrobial peptides) have pleiotropic immunomodulatory functions. The human host defense peptide LL-37 is up-regulated at sites of infection and has little or no antimicrobial activity in tissue-culture media but under the same conditions, demonstrates immunomodulatory effects on epithelial cells, monocytes, and dendritic cells (DC). These effects include the induction of chemokine production in a mitogen-activated protein kinase-dependent manner in epithelial cell lines and monocytes and profound alterations of DC differentiation, resulting in the capacity to enhance a T helper cell type 1 response. Although the exact mechanisms of interaction between LL-37 and these cell types have not been elucidated, there is evidence for specific (i.e., receptor-mediated) and nonspecific interactions. The relative significance of the direct antimicrobial activities and immunomodulatory properties of LL-37 and other cationic host defense peptides in host defense remains unresolved. To demonstrate that antimicrobial activity was not necessarily required for protection in vivo, model peptides were synthesized and tested for antimicrobial and immunomodulatory activities. A peptide with no antimicrobial activity was found to be protective in animal models of Staphylococcus aureus and Salmonella infection, implying that a host defense peptide can protect by exerting immunomodulatory properties.

Immunomodulatory effects of anti-microbial peptides

“…Like many HDPs, the human cathelicidin LL-37 (Table I) kills bacteria only in low-ionic strength solvents, and becomes inactive when tested in tissue culture media [75]. Actually, it is in the more physiological conditions when LL-37 exhibits a wide range of immunomodulatory properties in vitro and these activities can be recapitulated in animal models [76].…”

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

“…It has direct microbicidal activities against a wide range of bacteria, viruses, fungi, and protozoa in vitro (5)(6)(7)(8)(9)(10). In addition, its antimicrobial functions in vivo are significantly contributed by multiple immunomodulatory properties (11)(12)(13).…”

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

“…The spectrum of LL-37 activities includes many other immunomodulatory effects, such as chemotactic activation of monocytes, neutrophils, and T cells mediated through the G protein-coupled formyl peptide receptor-like 1 (8); airway epithelial cell IL-8 production, proliferation, and wound closure mediated by the epidermal growth factor receptor (9,10); and possibly IL-1b processing and release via direct activation of P2X7 receptors (11). The cellular mechanisms and signaling pathways involved in the multiple functions of LL-37 are of interest because they might provide new strategies for antibacterial and immunomodulatory drug development (12,13).…”