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1.
Cell Host Microbe ; 19(1): 21-31, 2016 Jan 13.
Article in English | MEDLINE | ID: mdl-26764594

ABSTRACT

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 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 genetically predisposed individuals.


Subject(s)
Gastrointestinal Microbiome , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Yersinia Infections/microbiology , Yersinia enterocolitica/physiology , Animals , Chronic Disease , Disease Progression , Female , Humans , Inflammatory Bowel Diseases/microbiology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Male , Mice , Mice, Knockout , Toll-Like Receptor 1/genetics , Toll-Like Receptor 1/immunology , Yersinia Infections/genetics , Yersinia Infections/immunology
2.
Innate Immun ; 21(8): 827-46, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26403174

ABSTRACT

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.


Subject(s)
Endothelium, Vascular/immunology , Immunity, Innate/physiology , Sepsis/immunology , Toll-Like Receptors/immunology , Blood Coagulation , Capillary Permeability , Endothelium, Vascular/metabolism , Humans , Sepsis/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
3.
Sci Signal ; 8(391): ra86, 2015 Aug 25.
Article in English | MEDLINE | ID: mdl-26307013

ABSTRACT

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-1ß (IL-1ß) 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.


Subject(s)
Human Umbilical Vein Endothelial Cells/immunology , Mitogen-Activated Protein Kinase 7/immunology , Monocytes/immunology , Systemic Inflammatory Response Syndrome/immunology , Animals , Human Umbilical Vein Endothelial Cells/pathology , Humans , Interleukin-1beta/immunology , Male , Mice , Monocytes/pathology , Systemic Inflammatory Response Syndrome/pathology , Systemic Inflammatory Response Syndrome/therapy , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/immunology , Tumor Necrosis Factor-alpha/immunology
4.
J Biol Chem ; 289(19): 13079-100, 2014 May 09.
Article in English | MEDLINE | ID: mdl-24644287

ABSTRACT

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.


Subject(s)
Analgesics/adverse effects , Arachidonic Acids/adverse effects , Benzoxazines/adverse effects , Cannabinoids/adverse effects , Dopamine/analogs & derivatives , Morpholines/adverse effects , Naphthalenes/adverse effects , Analgesics/pharmacology , Arachidonic Acids/pharmacology , Bacterial Proteins/toxicity , Benzoxazines/pharmacology , Cannabinoids/pharmacology , Dopamine/adverse effects , Dopamine/pharmacology , Human Umbilical Vein Endothelial Cells , Humans , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/pathology , Lipopeptides/toxicity , Morpholines/pharmacology , Naphthalenes/pharmacology , Receptors, Cannabinoid/metabolism , TRPV Cation Channels/metabolism
5.
J Exp Med ; 209(8): 1437-44, 2012 Jul 30.
Article in English | MEDLINE | ID: mdl-22778390

ABSTRACT

The balance between regulatory and inflammatory immune responses is critical to maintain intestinal homeostasis. Furthermore, the nature of the inflammatory response needs to be tailored to the tissue to provide proper protective immunity while preserving host integrity. TLR2 (Toll-like receptor 2) is a unique TLR in that it has been shown to promote regulatory and inflammatory T cell responses. Using Yersinia enterocolitica, we show that oral infection promotes T(H)17 immunity, whereas systemic infection promotes T(H)1 immunity. Furthermore, induction of T(H)17 immunity during oral infection is dependent on TLR1 and results from the combinatorial effect of TLR2/TLR1-induced IL-6 and IL-23 and the presence of TGF-ß in the intestinal environment. Interestingly, TLR2/TLR1 was not involved in T(H)1 immune responses during systemic infection, whereas the TLR2/TLR6 receptor complex induced IL-10(+) regulatory T cell responses during both systemic and oral infections. Our results reveal that the route of infection is central in determining which pathways provide protective immunity. Furthermore, they also demonstrate that TLR2 has dual immune functions in the gut and identify TLR1 as a critical innate receptor for protective intestinal T(H)17 immunity.


Subject(s)
Intestinal Mucosa/immunology , Th17 Cells/immunology , Toll-Like Receptor 1/immunology , Toll-Like Receptor 1/metabolism , Yersinia Infections/immunology , Yersinia enterocolitica/immunology , Animals , Inflammation/immunology , Inflammation/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-23/immunology , Interleukin-23/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Intestinal Mucosa/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/metabolism , Toll-Like Receptor 2/immunology , Toll-Like Receptor 2/metabolism , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism , Yersinia Infections/metabolism
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