A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Fort, Madeleine M.; Mozaffarian, Afsaneh; Stöver, Axel G.; Correia, Jean da Silva; Johnson, David A.; Crane, Ryan; Ulevitch, Richard J.; Persing, David H.; Bielefeldt‐Ohmann, Helle; Probst, Peter; Jeffery, Eric; Fling, Steven P.; Hershberg, Robert M.

doi:10.4049/jimmunol.174.10.6416

Cited by 205 publications

(154 citation statements)

References 38 publications

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“…6). These cells release cytoprotective factors such as IL-11 and IL-22, whose protective capacity against acute colitis has been demonstrated by direct administration or local gene delivery in WT animals (28,29). Myeloid cells, in particular, can contribute to protection against acute colitis, because their depletion exacerbated acute DSSinduced colitis (30).…”

Section: Discussionmentioning

confidence: 99%

Opposing functions of IKKβ during acute and chronic intestinal inflammation

Eckmann¹,

Nebelsiek

Fingerle

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

127

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Section: Discussionmentioning

confidence: 99%

Opposing functions of IKKβ during acute and chronic intestinal inflammation

Eckmann¹,

Nebelsiek

Fingerle

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

127

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“…Activation of TLRs by these molecules has been proven to play a key role in the development and progression of various chronic infectious diseases depending on the expression of TLRs at sites of contact with bacteria. For instance, the Asp299Gly polymorphism of TLR-4, which is expressed on intestinal epithelial cells, was recently associated with Crohn's disease (31), and a synthetic TLR-4 antagonist was shown to inhibit the development of 2 experimental models of inflammatory bowel disease (32). Despite the concerns regarding possible LPS contamination, it is currently believed that some damageassociated components of extracellular matrix can activate TLR-4, and it was therefore hypothesized that TLR-4 activation may also be involved in several noninfectious disease conditions based on the "danger model" of autoimmunity (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Abdollahi‐Roodsaz

Joosten

Roelofs

et al. 2007

Arthritis & Rheumatism

283

219

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Objective. Degeneration of extracellular matrix of cartilage leads to the production of molecules capable of activating the immune system via Toll-like receptor 4 (TLR-4). The objective of this study was to investigate the involvement of TLR-4 activation in the development and progression of autoimmune destructive arthritis.Methods. A naturally occurring TLR-4 antagonist, highly purified lipopolysaccharide (LPS) from Bartonella quintana, was first characterized using mouse macrophages and human dendritic cells (DCs). Mice with collagen-induced arthritis (CIA) and mice with spontaneous arthritis caused by interleukin-1 receptor antagonist (IL-1Ra) gene deficiency were treated with TLR-4 antagonist. The clinical score for joint inflammation, histologic characteristics of arthritis, and local expression of IL-1 in joints were evaluated after treatment.Results. The TLR-4 antagonist inhibited DC maturation induced by Escherichia coli LPS and cytokine production induced by both exogenous and endogenous TLR-4 ligands, while having no effect on these parameters by itself. Treatment of CIA using TLR-4 antagonist substantially suppressed both clinical and histologic characteristics of arthritis without influencing the adaptive anti-type II collagen immunity crucial for this model. Treatment with TLR-4 antagonist strongly reduced IL-1␤ expression in articular chondrocytes and synovial tissue. Furthermore, such treatment inhibited IL-1-mediated autoimmune arthritis in IL-1Ra ؊/؊ mice and protected the mice against cartilage and bone pathology.Conclusion. In the present study, we demonstrate for the first time that inhibition of TLR-4 suppresses the severity of experimental arthritis and results in lower IL-1 expression in arthritic joints. Our data suggest that TLR-4 might be a novel target in the treatment of rheumatoid arthritis.Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology associated with chronic inflammation of peripheral joints. Today it is generally accepted that proinflammatory cytokines play an important role in the pathogenesis of RA (1); however, the mechanisms of initiation and perpetuation of the inflammatory cascade in RA are still unknown.Toll-like receptors (TLRs) are a family of pattern recognition receptors that are involved in the recognition of conserved pathogen-associated molecular patterns (2). Ligand binding to TLRs initiates a signaling cascade that leads to the activation of the NF-B and interferon regulatory factor 3 transcription factors and MAPKs, which in turn promote the production of inflammatory cytokines, chemokines, and tissuedestructive enzymes and the expression of costimulatory molecules on antigen-presenting cells (APCs). These costimulatory molecules provide a second signal to T cells to initiate the adaptive immune response (3,4

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“…We confirmed this in TLR4Ϫ/Ϫ mice. In vitro, alteration of pulmonary microvascular endothelial cytoskeleton occurs during simulated ischemia-reperfusion; this was substantially reduced in our model by CRX-526, a competitive inhibitor of TLR4 (14), implying a possible mechanism for TLR4-mediated pulmonary edema due to IRI. Pretreatment of mice with CRX-526 also reduced edema formation.…”

mentioning

confidence: 94%

“…To model warm ischemia (WI), cell medium was suddenly replaced with 2 ml of nutrient-depleted clinical grade Ringer lactate (RL) containing 100 U/ml penicillin and 100 g/ml streptomycin, and the chamber was ventilated with 100% O2. Dishes were pretreated with 1 g/ml CRX-526 (GlaxoSmithKline, Duluth, MN), a competitive inhibitor of TLR4 (14), or vehicle (2% glycerin) 1 h before WI. CRX-526 or vehicle was added whenever medium was changed.…”

Section: Surgical Model Of Murine Lung Irimentioning

confidence: 99%

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

Zanotti

Casiraghi

Abano³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/ OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)-and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-B was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemiareperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability. microvascular permeability; endothelial cell; pulmonary edema ACUTE LUNG INJURY IS A FEATURE of sepsis, systemic inflammatory response, and adult respiratory distress syndrome. Noncardiogenic pulmonary edema and impaired gas exchange are consequences of acute lung injury, irrespective of etiology. The mechanisms causing pulmonary edema due to acute lung injury are not well-understood. Ischemia-reperfusion injury (IRI), a form of acute lung injury occurring immediately following lung transplantation, is a frequent complication causing morbidity and mortality (26). A greater understanding of lung IRI is likely relevant to many types of acute lung injury and thus may benefit not only lung transplant recipients, but also substantial numbers of other patients with lung injury. Such knowledge would also facilitate retrieval of lungs from nonheart-beating cadaver donors for transplant and/or may assist in the salvage of lungs not considered suitable for transplant, thereby reducing the critical shortage of transplantable lungs (8, 11).Reperfusion following an interval of ischemia results in an inflammatory response involving components of the innate immune system, including the complement and coagulation cascades. Both parenchymal and myeloid cells elaborate free radicals, nitric oxide, and pro-and anti-inflammatory cytokines (4, 5). Recently, there has been increasing awareness of the important contribution of the innate immune syst...

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A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Cited by 205 publications

References 38 publications

Opposing functions of IKKβ during acute and chronic intestinal inflammation

Opposing functions of IKKβ during acute and chronic intestinal inflammation

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

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