LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.
van der Does. Anne M AM; Beekhuizen. Henry H; Ravensbergen. Bep B; Vos. Tim T; Ottenhoff. Tom H M TH; van Dissel. Jaap T JT; Drijfhout. Jan W JW; Hiemstra. Pieter S PS; Nibbering. Peter H PH
Key Findings
- LL-37 shifts monocyte‑derived macrophages toward a pro‑inflammatory profile
- Maximum effect seen at 10 µg/ml when added from the beginning of culture
- The C‑terminal region of LL-37 drives this effect and requires internalization
Practical Outcomes
- LL-37 could be used to boost short‑term immune activation, but it also raises inflammation, so it’s not ideal for chronic anti‑aging or inflammation‑reduction strategies. Timing and dose matter, and the peptide isn’t widely available or stable, so more research is needed before practical use.
Summary
LL-37, a natural antimicrobial peptide, makes immune cells called macrophages more inflammatory, even when they would normally become calming types. The effect shows up best at about 10 µg/ml if the peptide is added right at the start of cell growth, and it needs the peptide to get inside the cells. The tail end of LL-37 does the work.
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.
Study Information
pubmed
2010
2010-07-07T00:00:00.000Z
10.4049/jimmunol.1000376
186
45