Deletion of TLR5 results in spontaneous colitis in mice

Vijay‐Kumar, Matam; Sanders, Catherine J.; Taylor, Roger R.; Kumar, Amrita; Aitken, Jesse D.; Sitaraman, Shanthi V.; Neish, Andrew S.; Uematsu, Satoshi; Akira, Shizuo; Williams, Ifor R.; Gewirtz, Andrew T.

doi:10.1172/jci33084

Cited by 287 publications

(351 citation statements)

References 28 publications

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“…The current body of literature suggests that altered composition of the gut microflora occurs in various genetically modified mouse strains, including IL-10 −/− , IL-22 −/− , and TLR5 −/− mice (9,18,19). Our study prompts inclusion of IL-23p19 −/− and IL-23R −/− in this list, because these mice have impaired IL-22 expression and harbor elevated amounts of SFB.…”

Section: Discussionmentioning

confidence: 77%

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

Shih¹,

Cox²,

Kljavin

et al. 2014

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

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Significance Commensal microbiota are known to be required for the elicitation of host Th17 responses, which may mediate autoimmune diseases. Here, we demonstrate that the IL-23 pathway dynamically regulates the abundance of certain commensals and maintains barrier function. Barrier disruption results in systemic dissemination of microbial products, which invokes the IL-23 pathway, with both beneficial and potentially deleterious consequences. Through induction of IL-22, IL-23 contributes to barrier repair, and through induction of the Th17 response, it aims to neutralize escaped commensal microbes. Thus, barrier disruption results in a pro-Th17 environment in which not only antimicrobial but also potentially antihost Th17 cells can develop.

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Section: Discussionmentioning

confidence: 77%

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

Shih¹,

Cox²,

Kljavin

et al. 2014

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

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“…However, potentially differential signaling induced by different TLRs complicates this hypothesis. For instance, Tlr5 -/-mice spontaneously develop colitis that is crucially mediated by TLR4 signaling [54] to beneficial and detrimental effects of signaling induced by TLR5 and TLR4, respectively. Despite these overall beneficial effects of TLR5 signaling, administration of TLR5 agonists in DSS-injured colons aggravates colitis, indicating that TLR5 signaling can also be deleterious in the intestine [55,56].…”

Section: Mechanisms Underlying the Dual Role Of Intestinal Nf-κb Actimentioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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“…Additional evidence for the role of TLRs in IBD comes from studies of flagellin and TLR-5. TLR-5-deficient mice, originally described by Uematsu et al, 60 develop spontaneous colitis, 61 suggesting that flagellin-TLR-5 interactions normally have a protective anti-inflammatory role. In contrast, in humans, a common polymorphism in TLR-5 that produces a dominant-negative receptor is protective against CD, but not UC, in people of Ashkenazi Jewish descent.…”

Section: Role For Altered Tlrs In Ibdmentioning

confidence: 99%

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

Himmel¹,

Hardenberg²,

Piccirillo³

et al. 2008

Immunology

129

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SummaryTwo related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4 + T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4 + T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease.

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Deletion of TLR5 results in spontaneous colitis in mice

Cited by 287 publications

References 28 publications

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota

NF-κB in the regulation of epithelial homeostasis and inflammation

The role of T‐regulatory cells and Toll‐like receptors in the pathogenesis of human inflammatory bowel disease

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