Cathelicidins Modulate TLR-Activation and Inflammation

Abstract

Cathelicidins are short cationic peptides that are part of the innate immune system. At first, these peptides were studied mostly for their direct antimicrobial killing capacity, but nowadays they are more and more appreciated for their immunomodulatory functions. In this review, we will provide a comprehensive overview of the various effects cathelicidins have on the detection of damage-and microbe-associated molecular patterns, with a special focus on their effects on Toll-like receptor (TLR) activation. We review the available literature based on TLR ligand types, which can roughly be divided into lipidic ligands, such as LPS and lipoproteins, and nucleic-acid ligands, such as RNA and DNA. For both ligand types, we describe how direct cathelicidin-ligand interactions influence TLR activation, by for instance altering ligand stability, cellular uptake and receptor interaction. In addition, we will review the more indirect mechanisms by which cathelicidins affect downstream TLR-signaling. To place all this information in a broader context, we discuss how these cathelicidin-mediated effects can have an impact on how the host responds to infectious organisms as well as how these effects play a role in the exacerbation of inflammation in auto-immune diseases. Finally, we discuss how these immunomodulatory activities can be exploited in vaccine development and cancer therapies.

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice

“…The existence of NETs has been reported in psoriatic skin, where they might play a role in inducing increased expression of human β-defensin-2 29 . Therefore, NETs and neutrophils can induce inflammation through various mechanisms, including inflammasome activation 30 , the triggering of Toll-like receptor 7 (TLR7) and TLR9 via self-antigen complexes such as cathelicidin antimicrobial peptide LL37 DNA 31 , macrophage pyroptosis stimulation 32 , and IL-36 cytokine processing and activation 33,34 .…”

Sequence Permutation Generates Peptides with Different Antimicrobial and Antibiofilm Activities

“…Although not general, cationic antimicrobial peptides frequently target bacterial membranes [ 2 , 3 , 4 , 5 , 6 , 7 ]. A fluorescence-based assay was performed for the determination the membrane active nature of peptides.…”

“…Antimicrobial peptides (AMPs, also called host defense peptides or innate immune peptides) are promising candidates as they can eliminate antibiotic-resistant pathogens, including those in the biofilm form [ 2 , 3 , 4 , 5 , 6 , 7 ]. AMPs have been discovered in the three life domains: bacteria, archaea, and eukarya.…”

“…In contrast, mammalian cells are rich in zwitterionic phosphocholines, which are less attractive to cationic AMPs. Such a lipid composition difference between host and pathogen membranes is believed to be the molecular basis for the cell selectivity of cationic AMPs, a requirement as novel medicine [ 2 , 3 , 4 , 5 , 6 , 7 ].…”

“…The isolation of potent antimicrobials from natural sources is an important approach [ 2 , 3 , 4 , 5 , 6 , 7 ]. Although labor-intensive, this classic approach has the great potential to identify novel candidates, including peptides [ 15 , 16 , 17 , 18 , 19 ].…”