title: Mincle activation enhances neutrophil migration and resistance to polymicrobial septic peritonitis.
abstract: Sepsis is a systemic inflammatory response to bacterial infection. The therapeutic options for treating sepsis are limited. Impaired neutrophil recruitment into the infection site is directly associated with severe sepsis, but the precise mechanism is unclear. Here, we show that Mincle plays a key role in neutrophil migration and resistance during polymicrobial sepsis. Mincle-deficient mice exhibited lower survival rates in experimental sepsis from cecal ligation and puncture and Escherichia coli-induced peritonitis. Mincle deficiency led to higher serum inflammatory cytokine levels and reduced bacterial clearance and neutrophil recruitment. Transcriptome analyses revealed that trehalose dimycolate, a Mincle ligand, reduced the expression of G protein-coupled receptor kinase 2 (GRK2) in neutrophils. Indeed, GRK2 expression was upregulated, but surface expression of the chemokine receptor CXCR2 was downregulated in blood neutrophils from Mincle-deficient mice with septic injury. Moreover, CXCL2-mediated adhesion, chemotactic responses, and F-actin polymerization were reduced in Mincle-deficient neutrophils. Finally, we found that fewer Mincle-deficient neutrophils infiltrated from the blood circulation into the peritoneal fluid in bacterial septic peritonitis compared with wild-type cells. Thus, our results indicate that Mincle plays an important role in neutrophil infiltration and suggest that Mincle signaling may provide a therapeutic target for treating sepsis.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Wook-Bin
authors.initials: WB
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Yan
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Quanri
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Won Young
authors.initials: WY
authors.lastname: Choi
authors.affiliation: Severance Biomedical Science Institute and BK21PLUS project to Medical Sciences, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Republic of Korea.|Severance Institute for Vascular and Metabolic Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Republic of Korea.
authors.forename: Lark Kyun
authors.initials: LK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.|Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D060085:Coinfection / Q000235:genetics* / Q000382:microbiology; D003311:Cord Factors / Q000235:genetics; D004926:Escherichia coli / Q000472:pathogenicity; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D020556:Neutrophil Infiltration / Q000235:genetics; D009504:Neutrophils / Q000382:microbiology; D010538:Peritonitis / Q000235:genetics* / Q000382:microbiology; D023063:Receptors, Interleukin-8B / Q000235:genetics; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology; D059467:Transcriptome / Q000235:genetics
chemical_list: C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D037181:Lectins, C-Type; D008565:Membrane Proteins; D023063:Receptors, Interleukin-8B; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2