Streptococcus Suis Serotype 2 Stimulates Neutrophil Extracellular Traps Formation via Activation of p38 MAPK and ERK1/2.

Fang Ma,Huixing Lin,Hongjie Fan,Hong Zhou,Zhe Ma,Xiaojing Chang,Guangyu Wang

doi:10.3389/fimmu.2018.02854

Abstract

Streptococcus suis serotype 2 is a major pathogen of swine streptococcicosis, which result in serious economic loss worldwide. SS2 is an important zoonosis causing meningitis and even death in humans. Neutrophil extracellular traps (NETs) constitute a significant bactericidal strategy of innate immune. The battle between SS2 and NETs may account for the pathogenicity of SS2. However, the molecular mechanism underlying release of SS2-induced NETs remains unclear. In this study, SS2 was found to induce NETs within 2–4 h, and was dependent on reactive oxygen species (ROS) from NADPH oxidase. Moreover, SS2 could activate neutrophil p38 MAPK and ERK1/2. Blockage of p38 MAPK or ERK1/2 activation decreased SS2-induced NETs formation by 65 and 85%, respectively. In addition, NADPH oxidase derived ROS inhibition negatively affected phosphorylation of p38 MAPK and ERK1/2 in SS2 induced neutrophils. Both TLR2 and TLR4 were significantly up-regulated by SS2 infection in blood cells in vivo and neutrophils in vitro, which indicates these two receptors are involved in SS2 recognition. Blocking TLR4 signaling could further inhibit the activation of ERK1/2, but not p38 MAPK; however, TLR4 signaling inhibition reduced NETs formation induced by SS2. In conclusion, SS2 could be recognized by TLR2 and/or TLR4, initiating NETs formation signaling pathways in a NADPH oxidase derived ROS dependent manner. ROS will activate p38 MAPK and ERK1/2, which ultimately induces NETs formation.

Highlights

Streptococcus suis serotype 2 (SS2) is a swine pathogen responsible for various diseases including meningitis, septicemia and even acute death; it is an important zoonotic pathogen causing serious invasive infections in humans worldwide
This result showed that SS2-induced Neutrophil extracellular traps (NETs) could be observed only at 180 min post infection (Figure 1), demonstrating that SS2-induced NETs release is not a quick process; this indicated that SS2-induced NETs formation likely belongs to the within 2–4 h classic model
To detect whether mitogen-activated protein kinase (MAPK)-p38, ERK and JNK were involved in SS2-induced NETs formation, neutrophils were infected with SS2 ZY05719 for 2 h, and phosphorylation of p38 MAPK, Extracellular signal related kinase 1/2 (ERK1/2), and JNK/SPAK were determined by western blot

Summary

Introduction

Streptococcus suis serotype 2 (SS2) is a swine pathogen responsible for various diseases including meningitis, septicemia and even acute death; it is an important zoonotic pathogen causing serious invasive infections in humans worldwide. Neutrophils are the most abundant immune cells among white blood cells, and play a vital role in defense against invasive pathogens and Neutrophil extracellular traps (NETs) are regarded as a significant bactericidal mechanism of innate immune system [4,5,6]. NETs are reticular fiber structures consisting of nuclear constituents and abundant bactericidal proteins, which will efficiently entrap and kill bacteria [7]. A variety of pathogens are reported to elicit NETs formation, and include Staphylococcus aureus (S. aureus) and Group A streptococcus [8, 9]. Bacteria, viruses, fungi, and such cytokines such as IL-8 can activate neutrophils and stimulate NETs release [4, 10, 11]

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