| First Author | Ode Y | Year | 2018 |
| Journal | J Leukoc Biol | Volume | 103 |
| Issue | 4 | Pages | 693-707 |
| PubMed ID | 29345380 | Mgi Jnum | J:259693 |
| Mgi Id | MGI:6148613 | Doi | 10.1002/JLB.3A0817-327RR |
| Citation | Ode Y, et al. (2018) CIRP increases ICAM-1(+) phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis. J Leukoc Biol 103(4):693-707 |
| abstractText | 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-kappaB 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. |
