期刊
JOURNAL OF INNATE IMMUNITY
卷 6, 期 3, 页码 325-338出版社
KARGER
DOI: 10.1159/000355888
关键词
Macrophages; Sepsis; Co-inhibitory molecule; Signal transduction; Migration; Phagocytosis
类别
资金
- NIH [GM46354, HL107149, R25 HL088992]
- 'W & F Hewlett' Summer Research Collaboration Fellowship
- NRSA fellowship [T32-GM65085]
- US Department of Education [GAANN-P200A100100]
The effect of programmed cell death receptor-1 (PD-1) on phagocyte function has not been extensively described. Here we report that experimental mouse sepsis, cecal ligation and puncture (CLP), induced a marked increase in peritoneal macrophage random migration, motility and cell spread, but these changes were lost in the absence of PD-1. Alternatively, phagocytic activity was inversely affected. In vitro cell culture imaging studies, with the macrophage cell line J774, documented that blocking PD-1 with antibody led to aggregation of the cytoskeletal proteins a-actinin and F-actin. Further experiments looking at ex vivo peritoneal macrophages from mice illustrated that a similar pattern of alpha-actinin and F-actin was evident on cells from wild-type CLP mice but not PD-1-/-CLP mouse cells. We also observed that fMLP-induced migration by J774 cells was markedly attenuated using PD-1 blocking antibodies, a nonselective phosphatase inhibitor and a selective Ras-related protein 1 inhibitor. Finally, peritoneal macrophages derived from CLP as opposed to Sham mice demonstrated aspects of both cell surface co-localization with CD11b and internalization of PD-1 within vacuoles independent of CD11b staining. Together, we believe the data support a role for PD-1 in mediating aspects of innate macrophage immune dysfunction during sepsis, heretofore unappreciated. (C) 2013 S. Karger AG, Basel
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