The endothelium forms a vast network that dynamically regulates vascular barrier function, coagulation pathways and vasomotor tone. Microvascular endothelial cells are uniquely situated to play key roles during infection and injury, owing to their widespread distribution throughout the body and their constant interaction with circulating blood. While not viewed as classical immune cells, endothelial cells express innate immune receptors, including the Toll-like receptors (TLRs), which activate intracellular inflammatory pathways mediated through NF-κB and the MAP kinases. TLR agonists, including LPS and bacterial lipopeptides, directly upregulate microvascular endothelial cell expression of inflammatory mediators. Intriguingly, TLR activation also modulates microvascular endothelial cell permeability and the expression of coagulation pathway intermediaries. Microvascular thrombi have been hypothesized to trap microorganisms thereby limiting the spread of infection. However, dysregulated activation of endothelial inflammatory pathways is also believed to lead to coagulopathy and increased vascular permeability, which together promote sepsis-induced organ failure. This article reviews vascular endothelial cell innate immune pathways mediated through the TLRs as they pertain to sepsis, highlighting links between TLRs and coagulation and permeability pathways, and their role in healthy and pathologic responses to infection and sepsis.

TLR1/TLR2 complexes are required for induction of IL-6 and IL-23 to generate protective TH17-mediated immunity and IgA production after oral but not systemic Yersinia enterocolitica infection.

Summary Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using a targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetic predisposed individuals.

Background:The endothelium is centrally involved in acute inflammatory disorders. Results: WIN55,212-2 and the endocannabinoid N-arachidonoyl dopamine (NADA), but not anandamide nor 2-arachidonoylglycerol, reduce endothelial activation by bacterial Toll-like receptor agonists and TNF␣. Conclusion: NADA is a newly identified endogenous regulator of endothelial inflammation. Significance: The endothelial endocannabinoid system represents a novel immune regulatory system that could be exploited therapeutically.

Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2). We inhibited the kinase activities and reduced the abundances of ERK5 and MEK5, a MAPK kinase directly upstream of ERK5, in primary human vascular endothelial cells and monocytes, and found that ERK5 promoted inflammation induced by a broad range of microbial TLR agonists and by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor–α (TNF-α). Furthermore, we found that inhibitors of MEK5 or ERK5 reduced the plasma concentrations of proinflammatory cytokines in mice challenged with TLR ligands or heat-killed Staphylococcus aureus, as well as in mice that underwent sterile lung ischemia-reperfusion injury. Finally, we found that inhibition of ERK5 protected endotoxemic mice from death. Together, our studies support a proinflammatory role for ERK5 in primary human endothelial cells and monocytes, and suggest that ERK5 is a potential therapeutic target in diverse disorders that cause inflammatory critical illness.