The Function And Mechanism Of Fpr2 Receptor Against Bacterial Infection By Regulating Neutrophils

Formyl peptide receptor（FPR）belongs to a class of G protein-coupled receptors（GPCR）.It belongs to the classical chemotactic GPCR subfamily and is expressed in various cell types,including neutrophils and macrophages.The activation of fpr2 can cause a series of signal transduction events,leading to myeloid cell migration,medium release,enhanced phagocytosis,new gene transcription,participation in the host response to bacterial infection,tissue repair and wound healing.Fpr2 is an important part of the innate immune response against bacterial infection.Studies evaluating Listeria monocytogenes,Staphylococcus aureus and Escherichia coli found that the host needs Fpr1/2 activation and inflammation to control bacteria.However,for Streptococcus suis and Streptococcus pneumoniae,Fpr2 activation aggravates the inflammatory damage of the host.Studies have found that Fpr2 activation can cause pro-inflammatory and anti-inflammatory effects.The most significant biological activity of Fpr2 is to induce leukocyte chemotaxis to migrate to the infected or injured area,which plays an important role in host defense and inflammation.However,the functional mechanism of Fpr2 in Streptococcus agalactiae and the regulation of the downstream signal pathway of Staphylococcus aureus infection have not been reported.Streptococcus agalactiae,also known as group B streptococcus（GBS）,can cause pneumonia,meningitis and bacteremia,making it a pathogen that can increase the risk of death in newborns and immunodeficient patients.Neutrophils are the first barrier of the host’s natural immune defense against these infections.Neutrophil recruitment to the site of infection is a key first step in the innate immune response to bacterial pathogens.The mechanism behind this process is not completely clear.We used the infection model induced by Streptococcus agalactiae（group B streptococcus,GBS）,a common gram-positive pathogen,to study neutrophil recruitment in vivo.This study found that mice without Fpr2 receptor were highly sensitive to GBS infection.These mice showed decreased chemotaxis to neutrophils,decreased neutrophils’bactericidal ability,and high mortality.RNAseq and Luminex analysis showed that Fpr2 activated key downstream signaling molecules and produced chemokine CXCL1/2 to chemotactic neutrophils.Like Fpr2^-/-,CXCL1/2 or neutrophil deletion impairs the host’s ability to resist GBS infection.In conclusion,these data suggest that Fpr2 contributes to the host’s ability to control GBS infection,and the lack of Fpr2 is related to the production of chemokines CXCL1 and CXCL2 and selective damage during neutrophil recruitment.Here,we clarify that Fpr2,as a chemotactic receptor,can not only directly act on chemotactic neutrophils,but also regulate the production of chemokines to control the infection of chemotactic neutrophils.This study may help to design strategies for the treatment of bacterial infection by enhancing the recruitment and functional activity of neutrophils.Staphylococcus aureus is an important bacterial pathogen,which can cause various respiratory infections in adults and children.Community-associated methicillin-resistant Staphylococcus aureus（CA-MRSA）bacteremia is highly resistant and highly virulence,and is highly correlated with high incidence rate and high mortality rate.The regulation of Fpr2 on downstream signaling pathway caused by Staphylococcus aureus infection is a very meaningful direction.We found that 30minutes after Staphylococcus aureus infected mouse neutrophils,a nuclear transcription factor,early transcription regulator EGR1,was highly expressed.EGR1 can regulate the transcription of many different functional genes,including biological functions such as cell cycle regulatory protein,extracellular matrix protein,transcription regulatory protein,cytokine and growth factor,due to regulate anti infection.We verified that Fpr2plays an important role in the upregulation of EGR1 by wrw4 inhibiting Fpr2 in vitro and Fpr2 knockout mice in vivo.Next,we inhibited ERK and Merk in vivo and in vitro.The results showed that the expression of EGR1 was significantly impaired after inhibition.The results showed that Fpr2 regulated ERK Fpr2 downstream.In the process of host resistance to Staphylococcus aureus infection,Fpr2 regulated EGR1expression through ERK and MERK pathways,for regulate the host to resist Staphylococcus aureus infection.In conclusion,our study found that Fpr2 plays an important regulatory role in the natural immune regulation in the process of bacterial infection.Fpr2 plays a positive regulatory role in dealing with the infection of Streptococcus agalactiae promotes neutrophils in natural immune cells to remove bacteria,so as to resist infection.Fpr2 receptor helps the host resist infection through downstream signal pathway in response to Staphylococcus aureus infection.We believe that Fpr2 receptor,as a key molecule in the process of host resistance to bacterial infection,is expected to become a target of antibacterial drugs.