Exogenous carbon monoxide inhibits neutrophil infiltration in LPS-induced sepsis by interfering with FPR1 via p38 MAPK but not GRK2.

Xu Wang,Mingming Song,Bingwei Sun,Yisen Zhang,Weiting Qin

doi:10.18632/oncotarget.9084

Abstract

Excessive neutrophil infiltration in vital organs is life-threatening to patients who suffer from sepsis. We identified a critical role of exogenous carbon monoxide (CO) in the inhibition of neutrophil infiltration during lipopolysaccharide (LPS)-induced sepsis. CO delivered from carbon monoxide-releasing molecule 2 (CORM-2) dramatically increased the survival rate of C57BL/6 mice subjected to LPS in vivo. CORM-2 significantly suppressed neutrophil infiltration in liver and lung as well as markers of inflammatory responses. Affymetrix GeneChip array analysis revealed that the increased expression of chemoattractant receptor formyl peptide receptor 1 (FPR1) may contribute to the excessive neutrophil infiltration. The under agarose migration assay demonstrated that LPS stimulation promoted migration to the ligand of FPR1, N-Formyl-Met-Leu-Phe (fMLP) but that CORM-2 treatment inhibited this promotion. Further studies demonstrated that CORM-2 internalized FPR1 by inhibiting p38 mitogen-activated protein kinase (MAPK) but not G protein-coupled receptor kinase 2 (GRK2), which may explain the inhibitory effect of CORM-2 on LPS-stimulated neutrophils. In summary, our study demonstrates that exogenous CO inhibits sepsis-induced neutrophil infiltration by interfering with FPR1 via p38 MAPK but not GRK2.

Highlights

Sepsis is a potentially life-threatening complication of infection with the presence of organ dysfunction [1,2,3]
Further studies demonstrated that carbon monoxide-releasing molecule 2 (CORM-2) internalized formyl peptide receptor 1 (FPR1) by inhibiting p38 mitogen-activated protein kinase (MAPK) but not G protein-coupled receptor kinase 2 (GRK2), which may explain the inhibitory effect of CORM-2 on LPS-stimulated neutrophils
CORM-2-treated septic mice exhibited a significantly increased survival rate of 68.75%. inactive CORM-2 (iCORM-2) administration failed to improve the survival of LPS mice

Summary

Introduction

Sepsis is a potentially life-threatening complication of infection with the presence of organ dysfunction [1,2,3]. Sepsis recently became the leading cause of death in intensive care units (ICUs) [4]. More than 250,000 people die of sepsis annually in the United States. This incidence is rising, despite the increasing input of medical resources [4]. Neutrophils are the first line of innate immune systems that eliminate pathogens in infectious foci [5,6,7]. Sepsisinduced immune disorder dramatically contributes to the excessive infiltration of neutrophils in distant organs, multiorgan dysfunction and death [8, 9]. Numerous studies have demonstrated that neutrophil depletion or the suppression of neutrophil migration rescued lethal sepsis [10, 11]

Methods

Results

Conclusion