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CIRP increases ICAM‐1 + phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis
Author(s) -
Ode Yasumasa,
Aziz Monowar,
Wang Ping
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3a0817-327rr
Subject(s) - sepsis , neutrophil extracellular traps , biology , inflammation , icam 1 , cd16 , immunology , neutrophile , phenotype , microbiology and biotechnology , cell adhesion molecule , gene , immune system , biochemistry , cd3 , cd8
Sepsis represents uncontrolled inflammation due to an infection. Cold‐inducible RNA‐binding protein (CIRP) is a stress‐induced damage‐associated molecular pattern (DAMP). A subset of neutrophils expressing ICAM‐1 + neutrophils was previously shown to produce high levels of reactive oxygen species. The role of CIRP for the development and function of ICAM‐1 + neutrophils during sepsis is unknown. We hypothesize that CIRP induces ICAM‐1 expression in neutrophils causing injury to the lungs during sepsis. Using a mouse model of cecal ligation and puncture (CLP)‐induced sepsis, we found increased expression of CIRP and higher frequencies and numbers of ICAM‐1 + neutrophils in the lungs. Conversely, the CIRP −/− mice showed significant inhibition in the frequencies and numbers of ICAM‐1 + neutrophils in the lungs compared to wild‐type (WT) mice in sepsis. In vitro treatment of bone marrow‐derived neutrophils (BMDN) with recombinant murine CIRP (rmCIRP) significantly increased ICAM‐1 + phenotype in a time‐ and dose‐dependent manner. The effect of rmCIRP on increasing frequencies of ICAM‐1 + neutrophils was significantly attenuated in BMDN treated with anti‐TLR4 Ab or NF‐κB inhibitor compared, respectively, with BMDN treated with isotype IgG or DMSO. The frequencies of iNOS producing and neutrophil extracellular traps (NETs) forming phenotypes in rmCIRP‐treated ICAM‐1 + BMDN were significantly higher than those in ICAM‐1 − BMDN. Following sepsis the ICAM‐1 + neutrophils in the lungs showed significantly higher levels of iNOS and NETs compared to ICAM‐1 − neutrophils. We further revealed that ICAM‐1 and NETs were co‐localized in the neutrophils treated with rmCIRP. CIRP −/− mice showed significant improvement in their survival outcome (78% survival) over that of WT mice (48% survival) in sepsis. Thus, CIRP could be a novel therapeutic target for regulating iNOS producing and NETs forming ICAM‐1 + neutrophils in the lungs during sepsis.