Abstract
Mast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense.
Highlights
Formation of extracellular traps (ETs) by several types of leukocytes occurs as a late antimicrobial response to the presence of microbial invaders or special chemicals [1, 2]
It should be noticed that the shape of MC extracellular trap (MCET) seems to differ according to the local tissue and testing environment which should be considered in the interpretation of results
Protocols for the investigation of ETs are overall similar for different innate immune cell populations, and the function of ETs is largely determined by the bioactivity and biofunction of peptides decorating the ejected DNA strands
Summary
Formation of extracellular traps (ETs) by several types of leukocytes occurs as a late antimicrobial response to the presence of microbial invaders (in vivo) or special chemicals (mostly reported in in vitro experiences) [1, 2]. Under the influence of growth factors such as stem cell factor (SCF), IL-3, IL-4, IL-9, IL-10, IL-33, and TGF-β [15], MC progenitors differentiate in functional mature cells that respond to a variety of environmental stimuli owing to expression of receptors including toll-like receptors and receptors to Fc portion of antibodies (such as FcεRI:IgE or FcγR: IgG) [16–18]. Beyond their classic role in allergic and anaphylactic reactions [19], MCs play an important role in microbial defense [12].
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