LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature

J Immunol. 2010 Aug 1;185(3):1442-9. doi: 10.4049/jimmunol.1000376. Epub 2010 Jul 7.

Abstract

The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MPhi-2; driven by M-CSF) versus proinflammatory macrophages (MPhi-1; driven by GM-CSF) as well as on fully differentiated MPhi-1 and MPhi-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 microg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF-driven macrophage differentiation. Exposure of fully differentiated MPhi-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MPhi-2. In contrast, LL-37 had no effect on fully differentiated MPhi-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antimicrobial Cationic Peptides / physiology*
  • Bacterial Infections / immunology
  • Bacterial Infections / pathology
  • Bacterial Infections / prevention & control
  • Cathelicidins
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Homeostasis / immunology
  • Humans
  • Inflammation / immunology
  • Inflammation / microbiology
  • Inflammation / prevention & control
  • Inflammation Mediators / physiology*
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / biosynthesis
  • Macrophage Colony-Stimulating Factor / physiology
  • Macrophages / classification
  • Macrophages / immunology*
  • Macrophages / pathology*
  • Molecular Sequence Data
  • Monocytes / cytology
  • Monocytes / immunology
  • Mycobacterium tuberculosis / immunology

Substances

  • Antimicrobial Cationic Peptides
  • Inflammation Mediators
  • Interleukin-10
  • Macrophage Colony-Stimulating Factor
  • Cathelicidins