Flagellin: key target of mucosal innate immunity

Vijay‐Kumar, Matam; Gewirtz, Andrew T.

doi:10.1038/mi.2009.9

Cited by 68 publications

(59 citation statements)

References 51 publications

(53 reference statements)

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“…TLR5 ligation in epithelial cells can activate a number of genes with anti-apoptotic functions (35). Therefore, flagellin is a key target of mucosal innate immunity (36). Bacterial flagellin can activate basolaterally expressed TLR5 to induce epithelial-driven inflammatory responses and proinflammatory gene expression.…”

Section: Discussionmentioning

confidence: 99%

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Xu¹,

Dong

et al. 2016

Ann. Transl. Med.

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Background: Ulcerative colitis (UC) is a nonspecific inflammatory disease for which medications and therapeutic strategies have only been moderately successful. CBLB502, a toll-like receptor 5 (TLR5) agonist derived from Salmonella flagellin, exhibits anticancer and radioprotective activities via modulation of TLRs and the nuclear factor kappa B (NF-κB) signaling pathway and can protect against acute renal ischemic failure. In this study, we intend to examine the effects of CBLB502 on both TLR responses and the interleukin (IL) and NF-κB signaling pathways in UC treatment.Methods: The UC mouse model was prepared in BALB/c mice by administering 2,4,6-trinitrobenzene sulfonic acid (TNBS). CBLB502 was used as the therapeutic drug. After CBLB502 therapy, the IL and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Total RNA and protein of colon samples was extracted.Results: We found that CBLB502 had a distinctive therapeutic effect in the UC model. In control group animals, IL-10 expression in serum was 91.48±24.38 ng/mL; this was higher than in the model group (59.36±14.46 ng/mL, P<0.05) or the treatment group (54.29±5.83 ng/mL, P<0.05). In model group animals, the concentration of TNF-α in serum was 140.11±12.70 ng/mL, which was lower than protein levels in the control group (173.86±29.26 ng/mL, P<0.05). The mRNA levels of TLR1,2,3,4,6,7,8, and 9 in the CBLB502 treatment group were significantly lower than in the model group (P<0.05). Western blot revealed that CBLB502 also reduced NF-κB expression in the mouse colon, but that NF-κB expression was not significantly lower than the model group.Conclusions: CBLB502 can reduce mucosal damage induced by TNBS and inhibit inflammation and TLR expression. The inhibition of UC by CBLB502 is strictly TLR-IL-dependent and is dose-dependent within the efficacious dose range. Therefore, our results suggested that CBLB502 might be a candidate drug for the treatment of UC.

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Section: Discussionmentioning

confidence: 99%

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Xu¹,

Dong

et al. 2016

Ann. Transl. Med.

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“…This flagella-mediated mucosal immune response is elicited via direct signaling through its cognate pattern-recognition receptor, Toll-like receptor 5 (14,15). Flagellin, a principal flagellar protein, continues to be implicated as a dominant antigen in CD and as a target of both innate and adaptive immune responses central to the immunopathogenesis of IBD (16,17).…”

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confidence: 99%

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Rooks

Veiga

Reeves

et al. 2016

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

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Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet −/− Rag2 −/− IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.colitis | Escherichia coli | QseC | antivirulence | gut microbiome

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“…[42][43][44] Surprising to us, however, is that such hematopoiesis was driven by TLR5-expressing cells in the bone marrow compartment ( Figures 3A-D and 4A-D). Given that, relative to other TLR agonists, flagellin preferentially activates hepatocytes and cells at mucosal surfaces (epithelial cells and mucosal CD11c 1 phagocytes), we had initially presumed that flagellin's impact on the bone marrow compartment was driven by its systemic induction of cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Such bias is in accord with observations that the most numerous and highly flagellin-responsive cell type, namely epithelial cells, produces copious amounts of neutrophil-attracting chemokines in response to flagellin. 6,21,42 Thus, a systemic exposure to flagellin would at once mobilize neutrophils to mucosal surfaces and activate production of these cells. 3 This explains our previous observation that repeated treatment of mice with flagellin over a 10-day period resulted in an enormous load of neutrophils in the intestine.…”

Section: Discussionmentioning

confidence: 99%