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- Title
Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection.
- Authors
Andonegui, Graciela; Hong Zhou; Bullard, Daniel; Kelly, Margaret M.; Mullaly, Sarah C.; McDonald, Braedon; Long, Elizabeth M.; Robbins, Stephen M.; Kubes, Paul; Zhou, Hong
- Abstract
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 EndotheliumTLR4 mice). Local administration of LPS into tissue induced comparable neutrophil recruitment in EndotheliumTLR4 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, EndotheliumTLR4 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 EndotheliumTLR4 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.
- Subjects
VASCULAR endothelial growth factors; MACROPHAGES; GRAM-negative bacteria; ENDOTHELIUM; ESCHERICHIA coli; GRAM-negative bacterial diseases; EPITHELIAL cells; CELL receptors; ANIMAL experimentation; CELL motility; COMPARATIVE studies; CYTOKINES; RESEARCH methodology; MEDICAL cooperation; MICE; MICROCIRCULATION; NEUTROPHILS; RESEARCH; RESEARCH funding; EVALUATION research; LIPOPOLYSACCHARIDES; PHYSIOLOGY; CELL physiology
- Publication
Journal of Clinical Investigation, 2009, Vol 119, Issue 7, p1921
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI36411