A Bacterial Flagellin,
            <i>Vibrio vulnificus</i>
            FlaB, Has a Strong Mucosal Adjuvant Activity To Induce Protective Immunity

Lee, Shee Eun; Kim, Soo Young; Jeong, Byung Chul; Kim, Young Ran; Bae, Soo Jang; Ahn, Ouk Seon; Lee, Je Jung; Song, Hee Jo; Kim, Jung Mogg; Choy, Hyon E.; Chung, Sun Sik; Kweon, Mi Na; Rhee, Joon Haeng

doi:10.1128/iai.74.1.694-702.2006

Cited by 205 publications

(201 citation statements)

References 41 publications

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“…Previous in vitro studies have suggested that TLR4-TLR5 heterodimers detect flagellin and then produce NO and IFN-b in a STAT1-dependent manner [19]. The CD14 receptor is also required to potentiate immunity in response to various TLR agonists, in a TLR4-independent process [48][49][50]. Our results clearly show that TLR4-and CD14-deficient mice respond to flagellin in the same way as WT mice do (Figs 1-3).…”

Section: Discussionsupporting

confidence: 75%

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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: Discussionsupporting

confidence: 75%

“…In contrast, flagellin may directly activate lung dendritic cells [48,56]. In systemic activation, dendritic cells are directly activated by flagellin in a MyD88-dependent manner [41,42] and this maturation is crucial for initiation of cellular and humoral adaptive immunity [57].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Intranasal administration of flagellins is known to promote mucosal adaptive immunity (14,22,26). To characterize the adjuvant properties of our recombinant molecules, Ab responses in serum and secretions were studied after i.n.…”

Section: Recombinant Flagellins Exhibit Mucosal Adjuvant Activitymentioning

confidence: 99%

Deletion of Flagellin’s Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity

Nempont

Cayet

Rumbo

et al. 2008

The Journal of Immunology

115

134

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TLRs trigger immunity by detecting microbe-associated molecular patterns (MAMPs). Flagellin is a unique MAMP because it harbors 1) an antigenic hypervariable region and 2) a conserved domain involved in TLR5-dependent systemic and mucosal proinflammatory and adjuvant activities. In this study, the contribution of the flagellin domains in TLR5 activation was investigated. We showed that TLR5 signaling can be neutralized in vivo by flagellin-specific Abs, which target the conserved domain. However, deletions of flagellin’s hypervariable region abrogated the protein’s intrinsic ability to trigger the production of neutralizing Abs. The fact that MAMP-specific Abs block TLR-mediated responses shows that this type of neutralization is a novel mechanism for down-regulating innate immunity. The stimulation of mucosal innate immunity and adjuvancy to foreign Ag was not altered by the hypervariable domain deletions. In contrast, this domain is essential to trigger systemic innate immunity, suggesting that there are distinct mechanisms for TLR5 activation in systemic and mucosal compartments. In summary, specific MAMP determinants control the production of neutralizing Abs and the compartmentalization of innate responses.

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“…Flagellin functions as an immunogen to induce strong immune response against itself and co-administered antigens. [16][17][18][37][38][39][40][41][42] Based on its biological properties, flagellin or flagellin-based fusion proteins are being developed as therapeutic agents or vaccines to treat infectious diseases, toxic exposures, and even cancer. [43][44][45][46][47] In recent years, studies have shown that the immune activities of flagellin, such as adjuvancy, are dependent on TLR5 recognition and the NLRC4 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin

Li¹,

Yang²,

Zhang³

et al. 2015

Cell Mol Immunol

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Bacterial flagellin is a unique pathogen-associated molecular pattern (PAMP), which can be recognized by surface localized Toll-like receptor 5 (TLR5) and the cytosolic NOD-like receptor (NLR) protein 4 (NLRC4) receptors. Activation of the TLR5 and/or NLRC4 signaling pathways by flagellin and the resulting immune responses play important roles in anti-bacterial immunity. However, it remains unclear how the dual activities of flagellin that activate the TLR5 and/or NLRC4 signaling pathways orchestrate the immune responses. In this study, we assessed the effects of flagellin and its mutants lacking the ability to activate TLR5 and NLRC4 alone or in combination on the adaptive immune responses against flagellin. Flagellin that was unable to activate NLRC4 induced a significantly higher antibody response than did wild-type flagellin. The increased antibody response could be eliminated when macrophages were depleted in vivo. The activation of NLRC4 by flagellin downregulated the flagellin-induced and TLR5-mediated immune responses against flagellin. Cellular & Molecular ImmunologyKeywords: flagellin; NLRC4; TLR5; macrophage; adaptive immunity INTRODUCTION Bacterial flagellin is one of a small number of protein pathogenassociated molecular patterns (PAMPs), which can be recognized by cell surface Toll-like receptor 5 (TLR5) 1 and the cytosolic NOD-like receptor protein 4 (NLRC4) inflammasome receptor NAIP5. 2,3 Flagellin consists of two highly conserved domains (D0 and D1) and one central hypervariable domain (D2/D3). [4][5][6] The conserved D0 and D1 domains are required for the immune activity of flagellin as a PAMP. The Nterminal amino acids 90-97 (QRVRELAV) of D1 form a highly conserved motif that is essential for both high-affinity binding and signaling to TLR5. 7,8 The C-terminal 35 amino acids of flagellin in the D0 domain are responsible for the interaction between flagellin and NLRC4. The substitution of three conserved leucine residues L502, L504, and L505 for alanine in the 35 C-terminal amino acids could abolish the ability of flagellin to activate NLRC4. 9 Flagellin-mediated activation of TLR5 activates inflammatory genes via the MyD88 pathway, whereas flagellin-activated NLRC4 triggers the assembly of the inflammasome, which culminates in caspase-1 activation, IL-1b/IL-18 secretion, and cellular pyroptosis. 10,11

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A Bacterial Flagellin, Vibrio vulnificus FlaB, Has a Strong Mucosal Adjuvant Activity To Induce Protective Immunity

Cited by 205 publications

References 41 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

Deletion of Flagellin’s Hypervariable Region Abrogates Antibody-Mediated Neutralization and Systemic Activation of TLR5-Dependent Immunity

Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin

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