期刊
PLOS ONE
卷 12, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0188882
关键词
-
资金
- National Institutes of Health [GM104323, GM109779, GM113228, GM072808, GM095442, GM117895, GM110537]
- Shock Society Research Fellowship for Early Career Investigators
Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naive CD4(+) and CD8(+) T cells and CD4(+) central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4(+) and CD8(+) T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1(+) LAG-3(+) 2B4(+) cells, suggesting that blockade of CXCR4 mitigates CD4(+) T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.
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