Cathelicidin peptide LL-37 modulates TREM-1 expression and inflammatory responses to microbial compounds

Gimano D. Amatngalim, Anastasia Nijnik, Pieter S. Hiemstra, Robert Hancock

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Inflammatory diseases remain an important cause of morbidity and mortality. Cathelicidins are immunomodulatory and antimicrobial peptides with potent anti-endotoxic properties. Although the effects of the human cathelicidin LL-37 on cellular responses to Toll-like receptor (TLR) ligands have been investigated, its effects on responses to other pro-inflammatory stimuli have not been well studied. Triggering receptor expressed on myeloid cells (TREM-1) acts to amplify inflammatory responses and plays important roles in the pathogenesis of endotoxemia. In this work, the effects of LL-37 on responses to TREM-1 stimulation, alone and in the presence of a range of microbial compounds, were analyzed. It was shown that in peripheral blood mononuclear cells LL-37 strongly suppressed synergistic responses to TREM-1 and TLR4 stimulation, partly through the inhibition of TREM-1 expression on monocytes; similar effects were observed using the TLR2 ligand lipoteichoic acid. In contrast, LL-37 stimulated TREM-1 upregulation by peptidoglycan (PGN, TLR2 ligand that is also recognized via nucleotide-binding oligomerization domain containing 2 after fragmentation and intracellular uptake), as well as the responses to combined TREM-1 and PGN stimulation, possibly via the p38 mitogen-activated protein kinase pathway. LL- 37 did not affect TREM-1-induced neutrophil degranulation or the production of reactive oxygen species and interleukin-8 by neutrophils. These findings provide further insight into the roles of LL- 37 during inflammation and may have implications for its in vivo immunomodulatory properties and for the design of synthetic cathelicidin derivatives as anti-inflammatory and anti-endotoxic molecules.

LanguageEnglish
Pages412-425
Number of pages14
JournalInflammation
Volume34
Issue number5
DOIs
Publication statusPublished - 1 Oct 2011

Keywords

  • Inflammation
  • LL-37
  • Lipopolysaccharide
  • Triggering receptor expressed on myeloid cells 1 (TREM-1)
  • cathelicidin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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