Targeting junctional adhesion molecule-C ameliorates sepsis-induced acute lung injury by decreasing CXCR4 + aged neutrophils

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Yohei Hirano¹  Yasumasa Ode¹  Mahendar Ochani¹  Ping Wang¹  Monowar Aziz¹ 

[1] Center for Immunology and Inflammation, Feinstein Institute for Medical Research;Department of Emergency and Critical Care Medicine, Juntendo University and Urayasu Hospital;Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

关键词: acute lung injury;    apoptosis;    CXCR4;    junctional adhesion molecule-C;    neutrophil aging;    sepsis;    transmigration;   

DOI  :  10.1002/JLB.3A0218-050R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Sepsis is a severe inflammatory condition associated with high mortality. Transmigration of neutrophils into tissues increases their lifespan to promote deleterious function. Junctional adhesion molecule-C (JAM-C) plays a pivotal role in neutrophil transmigration into tissues. We aim to study the role of JAM-C on the aging of neutrophils to cause sepsis-induced acute lung injury (ALI). Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP) and JAM-C expression in serum was assessed. Bone marrow-derived neutrophils (BMDN) were treated with recombinant mouse JAM-C (rmJAM-C) ex vivo and their viability was assessed. CLP-operated animals were administrated with either isotype IgG or anti-JAM-C Ab at a concentration of 3 mg/kg and after 20 h, aged neutrophils (CXCR4+) were assessed in blood and lungs and correlated with systemic injury and inflammatory markers. Soluble JAM-C level in serum was up-regulated during sepsis. Treatment with rmJAM-C inhibited BMDN apoptosis, thereby increasing their lifespan. CLP increased the frequencies of CXCR4+ neutrophils in blood and lungs, while treatment with antiJAM-C Ab significantly reduced the frequencies of CXCR4+ aged neutrophils. Treatment with anti-JAM-C Ab significantly reduced systemic injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as systemic and lung inflammatory cytokines (IL-6 and IL-1?) and chemokine (macrophage inflammatory protein-2). The blockade of JAM-C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro-inflammatory aged neutrophils by blockade of JAM-C has a novel therapeutic potential in sepsis-induced ALI.

【 授权许可】

CC BY