Host Defense Peptides LL-37 and Lactoferrin Trigger ET Release from Blood-Derived Circulating Monocytes

Frederic V Schwäbe,Lotta Happonen,Sofie Ekestubbe,Ariane Neumann

doi:10.3390/biomedicines10020469

Abstract

Neutrophils are commonly regarded as the first line of immune response during infection or in tissue injury-induced inflammation. The rapid influx of these cells results in the release of host defense proteins (HDPs) or formation of neutrophil extracellular traps (NETs). As a second wave during inflammation or infection, circulating monocytes arrive at the site. Earlier studies showed that HDPs LL-37 and Lactoferrin (LTF) activate monocytes while neutrophil elastase facilitates the formation of extracellular traps (ETs) in monocytes. However, the knowledge about the impact of HDPs on monocytes remains sparse. In the present study, we investigated the effect of LL-37 and LTF on blood-derived CD14+ monocytes. Both HDPs triggered a significant release of TNFα, nucleosomes, and monocyte ETs. Microscopic analysis indicated that ET formation by LL-37 depends on storage-operated calcium entry (SOCE), mitogen-activated protein kinase (MAPK), and ERK1/2, whereas the LTF-mediated ET release is not affected by any of the here used inhibitors. Quantitative proteomics mass spectrometry analysis of the neutrophil granular content (NGC) revealed a high abundance of Lactoferrin. The stimulation of CD14+ monocytes with NGC resulted in a significant secretion of TNFα and nucleosomes, and the formation of monocyte ETs. The findings of this study provide new insight into the complex interaction of HDPs, neutrophils, and monocytes during inflammation.

Highlights

In response to bacterial invasion or tissue injuries, neutrophils undergo the process of degranulation, releasing a broad range of proteins from distinct granules [1]
The present study identified a novel role for host defense proteins (HDPs) LL-37 and LTF, triggering the release of extracellular traps from CD14+ monocytes
Janardhan et al previously proposed a correlation between neutrophil-associated HDPs and monocyte recruitment [8], which was later confirmed by Soehnlein et al [12]

Summary

Introduction

In response to bacterial invasion or tissue injuries, neutrophils undergo the process of degranulation, releasing a broad range of proteins from distinct granules [1]. While usually being considered short-lived cells, neutrophils display an unnormal prolonged life span during chronic inflammation [2]. Upon stimulation by neutrophil or endothelial secretion products, e.g., due to a microbial breach [3], circulating monocytes arrive as a second wave of immune cells. Due to their plasticity, monocyte behavior is majorly distinct to the tissue environment [4]. Monocyte behavior is majorly distinct to the tissue environment [4] They account for around 10% of all leukocytes [5]. Monocytes are traditionally divided into three sup-populations, dependent on their expression of the surface markers CD14 and CD16 [5]

Methods

Results

Conclusion