Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

被引:135
作者
Andonegui, Graciela
Zhou, Hong
Bullard, Daniel [2 ]
Kelly, Margaret M.
Mullaly, Sarah C.
McDonald, Braedon
Long, Elizabeth M. [3 ,4 ]
Robbins, Stephen M. [3 ,4 ]
Kubes, Paul [1 ]
机构
[1] Univ Calgary, Dept Physiol & Biophys, Immunol Res Grp, Snyder Inst Infect Immun & Inflammat,Fac Med, Calgary, AB T2N 4N1, Canada
[2] Univ Alabama, Dept Genet, Birmingham, AL USA
[3] Univ Calgary, Fac Med, Dept Oncol, Calgary, AB T2N 4N1, Canada
[4] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada
关键词
NF-KAPPA-B; TOLL-LIKE RECEPTOR-4; IN-VIVO; DIFFERENTIAL EXPRESSION; LEUKOCYTE RECRUITMENT; DENDRITIC CELLS; PRIMARY CULTURE; SEPTIC SHOCK; E-SELECTIN; NEUTROPHIL;
D O I
10.1172/JCI36411
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Recognition of LPS by TLR4 on immune sentinel cells such as macrophages is thought to be key to the recruitment of neutrophils to sites of infection with Gram-negative bacteria. To explore whether endothelial TLR4 plays a role in this process, we engineered and imaged mice that expressed TLR4 exclusively on endothelium. (known herein as Endothelium(TLR4) mice). Local administration of LPS into tissue induced comparable neutrophil recruitment in Endothelium(TLR4) and wild-type mice. Following systemic LPS or intraperitoneal E. coli administration, most neutrophils were sequestered in the lungs of wild-type mice and did not accumulate at primary sites of infection. In contrast, Endothelium(TLR4) mice showed reduced pulmonary capillary neutrophil sequestration over the first 24 hours; as a result, they mobilized neutrophils to primary sites of infection, cleared bacteria, and resisted a dose of E. coli that killed 50% of wild-type mice in the first 48 hours. In fact, the only defect we detected in Endothelium(TLR4) mice was a failure to accumulate neutrophils in the lungs following intratracheal administration of LPS; this response required TLR4 on bone marrow-derived immune cells. Therefore, endothelial TLR4 functions as the primary intravascular sentinel system for detection of bacteria, whereas bone marrow-derived immune cells are critical for pathogen detection at barrier sites. Nonendothelial TLR4 contributes to failure to accumulate neutrophils at primary infection sites in a disseminated systemic infection.
引用
收藏
页码:1921 / 1930
页数:10
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