Flagellin Is the Major Proinflammatory Determinant of Enteropathogenic <i>Salmonella</i>

Zeng, Hui; Carlson, Adam; Guo, Yanwen; Yu, Yimin; Collier-Hyams, Lauren S.; Madara, James L.; Gewirtz, Andrew T.; Neish, Andrew S.

doi:10.4049/jimmunol.171.7.3668

Cited by 204 publications

(214 citation statements)

References 38 publications

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“…A variety of studies have demonstrated that lung and intestinal epithelial cells respond to flagellin by producing PMN-specific chemokines (CXCL1, CXCL5 or CXCL8), cytokines (TNF-a and IL-6) and antimicrobial molecules (NO and h-bD2) [18]. These findings agree with TLR5's predominant expression in lung and intestinal epithelial cells; hence, the epithelium is considered to be one of the main TLR5-responsive compartments [34,35]. Here, we used Salmonella typhimurium flagellin and its cognate detector TLR5 as models for investigating the contribution of radioresistant and radiosensitive cells to lung innate immunity.…”

Section: Discussionmentioning

confidence: 65%

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

et al. 2009

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Bacterial products (such as endotoxins and flagellin) trigger innate immune responses through TLRs. Flagellin-induced signalling involves TLR5 and MyD88 and, according to some reports, TLR4. Whereas epithelial and dendritic cells are stimulated by flagellin in vitro, the cell contribution to the in vivo response is still unclear. Here, we studied the respective roles of radioresistant and radiosensitive cells in flagellin-induced airway inflammation in mice. We found that i.n. delivery of flagellin elicits a transient change in respiratory function and an acute, pro-inflammatory response in the lungs, characterized by TLR5-and MyD88-dependent chemokine secretion and neutrophil recruitment. In contrast, TLR4, CD14 and TRIF were not essential for flagellin-mediated responses, indicating that TLR4 does not cooperate with TLR5 in the lungs. Respiratory function, chemokine secretion and airway infiltration by neutrophils were dependent on radioresistant, TLR5-expressing cells. Furthermore, lung haematopoietic cells also responded to flagellin by activating TNF-a production. We suggest that the radioresistant lung epithelial cells are essential for initiating early, TLR5-dependent signalling in response to flagellin and thus triggering the lung's innate immune responses.Key words: Chemokine . Epithelium . Flagellin . Lung inflammation . TLR5 IntroductionUpon challenge with respiratory pathogens, the airways rapidly develop a pro-inflammatory response initiated by environmental agents including microbe-associated molecular patterns such as Gram-negative bacteria LPS or endotoxins. This proinflammatory reaction plays an important role in the innate defense against respiratory pathogens [1,2]. Physiological changes induced by endotoxin inhalation include pulmonary Ã These authors contributed equally to this work. Eur. J. Immunol. 2009. 39: 1587-1596 DOI 10.1002 Innate immunity 1587 function and bronchoconstriction, cytokine and chemokine production, PMN recruitment, increased permeability of the alveolar epithelium and the associated endothelium [3][4][5][6]. TLR4 [7], together with MD-2, LPS-binding protein and CD14 detect endotoxins and play a critical role in the initiation of the pulmonary response to systemic and mucosal endotoxin administration [5,[8][9][10]. The pulmonary inflammation to endotoxin involves TLR4 signalling in both the parenchyma cells like endothelial and epithelial cells and the haematopoietic cells, i.e. monocytes, dendritic cells and neutrophils [11]. In addition, TLR4 signalling contributes to the development and progression of chronic respiratory disease including asthma [12][13][14][15][16].Flagellin is the major constituent of flagella from Gramnegative and Gram-positive bacteria. TLR5 has been identified as the main pattern recognition receptor required for flagellinmediated immune signalling [17]. TLR5 signalling depends on MyD88 and results in activation of MAPK, nuclear translocation of NF-kB and production of various pro-inflammatory cytokines and chemokines [18]. Moreover, a previous ...

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Section: Discussionmentioning

confidence: 65%

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

et al. 2009

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“…TLR5 is one member of the TLR family of transmembrane receptors that recognize a broad variety of ligands termed pathogen associated molecular patterns (PAMPs) [13]. Recognition of Salmonella flagellin by TLR5, which is broadly expressed in many cell types including epithelial cells, results in the induction of proinflammatory cytokines and chemokines [14][15][16][17]. Cytosolic flagellin requires Ipaf for activation of caspase-1 and IL-1β secretion in Salmonella infected macrophages [11,12].…”

Section: Introductionmentioning

confidence: 99%

Activation of NF-κB-dependent gene expression by Salmonella flagellins FliC and FljB

Simon

Samuel

2007

Biochemical and Biophysical Research Communications

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Bacterial flagellin is recognized by Toll-like receptor (TLR5) and activates NF-κB which leads to the induction of proinflammatory gene expression. Salmonella expresses two flagellin proteins, FliC and FljB. We purified FliC and FljB and examined the ability of the Salmonella flagellins to activate the NF-κB transcription factor in human embryonic kidney cells. We found that FliC and FljB as purified proteins possessed a comparable specific activity for activation of NF-κB-dependent gene expression in HEK293 cells. We also determined the ability of UV-inactivated bacteria, both wildtype and fliC and fljB mutant strains, to activate NF-κB. Wild-type fliC + /fljB + Salmonella and the fliC + /fljB − mutant strain were robust activators, whereas the fliC − /fljB + and flhC − mutant strains were very poor activators. The NF-κB activation capacity of bacterial strains correlated with their flagellin expression level. Finally, Salmonella cell wall-associated polymeric flagellin displayed greatly reduced ability to activate NF-κB compared to purified monomeric flagellin.

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“…Induction of IL-1β and IL-8 mRNA in ileal PP correlated with migration of neutrophils to the mucosa, 6 h after intragastric inoculation of pigs with Salmonella serovar Choleraesuis χ3246 (Hyland et al, unpublished data). Salmonella-mediated induction of IL-1β and IL-8 has been demonstrated in epithelial cell lines and in the jejunum of chickens, which do not have Peyer's patches (McCormick et al, 1993;Withanage et al, 2004;Zeng et al, 2003). Salmonella serovar Typhimurium infection of ligated intestinal loops in mice increases mRNA levels of IL-1, TNFα, and IL-6 along with secretion of TNFα protein (Arnold et al, 1993;Klimpel et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1β and IL-8 expression

Hyland

Brown

Murtaugh

2006

Veterinary Immunology and Immunopathology

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Salmonella enterica serovar Choleraesuis is an enteric pathogen of swine, producing septicemia, enterocolitis, pneumonia, and hepatitis. The initial molecular events at the site of Salmonella infection are hypothesized to be critical in the initiation of innate and adaptive immune responses; however the acute immune response elicited by porcine intestinal tissues is not well understood. To address this need, we employed explants of jejunal Peyer's patch (JPP) mucosa from pigs to examine Salmonella-induced immune responses under controlled conditions as well as to overcome limitations of whole animal approaches. JPP explants mounted in Ussing chambers maintained normal histological structure for 2 h and stable short-circuit current and electrical conductance for 2.5 h. After ex vivo luminal exposure to Salmonella serovar Choleraesuis, JPP responded with an increase in mRNA expression of IL-1β and IL-8, but not TNFα. Increased IL-1β and IL-8 expression were dependent on efficient Salmonella adhesion and internalization, whereas mutant Salmonella did not induce inflammatory cytokine expression. Commensal enteric bacteria, present in some experiments, also did not induce inflammatory cytokine expression. These findings indicate that Salmonella uptake by Peyer's patch is important in the induction of an innate response involving expression of IL-1β and IL-8, and that ex vivo intestinal immune tissue explants provide an intact tissue model that will facilitate investigation of mucosal immunity in swine.Keywords animal models; swine; cytokines; interleukins; mucosal immunology IntroductionSalmonella enterica represents a serologically diverse group of enteric pathogens capable of infecting both animals and humans. Salmonella serovar Choleraesuis is a major enteric pathogen in swine which produces septicemia, enterocolitis, pneumonia, and hepatitis, and is a common cause of systemic disease (Schwartz, 1999). Ingested Salmonella invade epithelial cells of the small intestine, including those of the gut-associated lymphoid tissue (GALT). Peyer's patches and mesenteric lymph nodes constitute a part of the organized GALT which provides specific, acquired immune defense against bacterial pathogens (Mowat, 2003).*To whom correspondence should be addressed at: Department of Veterinary and Biomedical Sciences, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN 55108, USA. Tel: 612-625-6735, Fax: 612-625-5203, email: murta001@umn.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. To date, the innate mucosal immune response to Salmonella has not been described in pig...

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Flagellin Is the Major Proinflammatory Determinant of Enteropathogenic Salmonella

Cited by 204 publications

References 38 publications

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

Activation of NF-κB-dependent gene expression by Salmonella flagellins FliC and FljB

Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1β and IL-8 expression

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