Elucidation of toll-like receptor and adapter protein signaling in vascular dysfunction induced by gram-positive Staphylococcus aureus or gram-negative Escherichia coli.
Pathogens contain specific pathogen-associated molecular patterns, which activate pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs). Although there is a clear evidence of how macrophages sense pathogens, we know less about such processes in vessels. This is critical to understand because activation of vascular cells and the subsequent induction of inflammatory genes by bacteria are crucial events in the development of septic shock. In the current study we have used genetically modified mice to investigate the role of TLRs, adapter proteins, tumor necrosis factor alpha (TNFalpha), and nitric oxide synthase II (NOSII) in vascular dysfunction induced by Gram-positive (Staphylococcus aureus) or Gram-negative (Escherichia coli) bacteria. Our data show that Gram-positive S. aureus or Gram-negative E. coli causes vascular dysfunction via the induction of NOSII. For S. aureus, this process requires TLR2, TLR6, myeloid differentiation factor 88 (MyD88) adapter-like, MyD88, and TNF, but not TLR4 or TLR1. Vascular dysfunction induced by E. coli requires TLR4 but has no requirement for TLR2, TLR1, TLR6, or TNF, and a partial but incomplete requirement of MyD88 and TIR domain-containing adapter inducing interferon-beta. Staphylococcus aureus induced NOSII protein expression in vascular smooth muscle cells but not in macrophages, whereas E. coli induced NOSII in both cell types. Our data are the first to establish the definitive roles of specific TLRs in the sensing of Gram-positive and Gram-negative bacteria by vessels and demonstrate that macrophages and blood vessels may differ in their response to pathogens.
Cartwright
Neil
N
Department of Critical Care, National Heart and Lung Institute, Imperial College, London, UK.
McMaster
Shaun K
SK
Sorrentino
Rosalinda
R
Paul-Clark
Mark
M
Sriskandan
Shiranee
S
Ryffel
Bernhard
B
Quesniaux
Valerie F J
VF
Evans
Timothy W
TW
Mitchell
Jane A
JA
D000818:Animals; D002478:Cells, Cultured; D004926:Escherichia coli / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013211:Staphylococcus aureus / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*; D014652:Vascular Diseases / Q000382:microbiology / Q000473:pathology*
D051193:Toll-Like Receptors; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse