SUPERSTOCK

It is widely accepted that lipopolysaccharide (LPS) shed from Gram-negative bacteria is recognized by Toll-like receptor 4 (TLR4) on cells such as tissue macrophages, leading to the recruitment of neutrophils to the site of infection, which is a hallmark of the innate immune response. Now, Andonegui and colleagues show that endothelial cells, rather than macrophages, are the key sentinel cells for detecting infection by Gram-negative bacteria and recruiting neutrophils to peripheral tissues.

Endothelial cells can express TLR4 and receptors for tumour necrosis factor and interleukin-1 (cytokines that are released by macrophages after the detection of bacteria), so they can detect and respond to LPS directly or indirectly. To test the role of TLR4 on endothelial cells in detecting LPS and initiating innate immune responses, the authors generated mice in which TLR4 was expressed exclusively on endothelium (Endothelium^TLR4 mice). Intravital microscopy showed that local administration of LPS into muscle resulted in the activation of endothelial cell TLR4 and the recruitment of neutrophils. By contrast, Endothelium^TLR4 mice could not respond to intratracheal administration of LPS, suggesting that activation of the endothelium alone was not sufficient to recruit neutrophils into the alveoli, where a barrier exists between the microvasculature and the site of LPS administration. Systemic administration of LPS in both wild-type and Endothelium^TLR4 mice resulted in a reduction in the number of circulating neutrophils, which were sequestered in the lungs but did not migrate into the alveoli or lung parenchyma. In wild-type mice the sequestered neutrophils stayed in the lungs, but in Endothelium^TLR4 mice the neutrophils were released back into the circulation after 24 hours. When wild-type mice were infected intraperitoneally with the Gram-negative bacterium Escherichia coli, bacteria were detectable in the lungs in 30 minutes. Half of the wild-type mice died in 48 hours; the surviving mice cleared bacteria from the lungs in 70 hours and from the peritoneum in a week. By contrast, Endothelium^TLR4 mice all survived the infection and cleared peritoneal bacteria in 48 hours. So, infection that results in prolonged pulmonary sequestration of neutrophils in wild-type mice prevents neutrophils from migrating to the primary site of infection.

These results show that TLR4-expressing endothelial cells are sufficient for intravascular detection of bacteria but that bone marrow-derived cells are required to detect bacteria at barrier-protected sites such as the lungs. This work has implications for understanding sepsis, which results in the death of 30–40% of patients, primarily owing to lung failure.

Author: Elaine Bell - Copyright © 2009 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission