Flagellin as an Adjuvant: Cellular Mechanisms and Potential

Mizel, Steven B.; Bates, John T.

doi:10.4049/jimmunol.1002156

Cited by 341 publications

(321 citation statements)

References 76 publications

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“…Flagellin-triggered responses exert various effects on different cells, tissues and organs; these responses vary greatly according to the dose, physiological condition of the cell, the animal used and the experimental setting. 15,17,26 However, the beneficial flagellinactivated responses for host defenses and the potential adverse effects of flagellin in different organs can be contradictory. Therefore, the flagellin-triggered pathophysiological responses should be explored further to provide a clearer understanding of the correlation between the pattern recognition receptors (PRRs)-flagellin interaction and its pathophysiological effects to enhance the application of recombinant flagellin as a prophylactic and therapeutic agent.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, an increasing number of studies have used flagellin as an adjuvant because of its ability both to promote cytokine production by a range of innate cell types and to trigger adaptive immune responses in a manner that is distinct from cognate antigen recognition. 15 Furthermore, flagellin has the potential to be used as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. 6 Vijay-Kumar et al 16 demonstrated that the systemic administration of flagellin might be a relatively safe means of providing temporary nonspecific protection against chemical, bacterial, viral and radiation challenge.…”

Section: Introductionmentioning

confidence: 99%

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Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

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Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for vaccines, and it might function as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated flagellin in the occurrence of some inflammatory diseases, such as acute lung inflammation, cardiovascular collapse and inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-TLR5 signaling activation plays a role in the pathophysiology of liver or whether some other flagellin activity also contributes to liver injury either via bacterial infections or during clinical applications. Recombinant flagellin proteins with or without TLR5-stimulating activity were used to evaluate the role of flagellin-TLR5 signaling in liver injury in wild-type and TLR5 KO mice. Gross lesions and large areas of hepatocellular necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 mg flagellin (FliC) in a dose-and time-dependent manner in wild-type mice, but not in TLR5 KO mice. Deletion of the N-terminal or TLR5 binding domain of flagellin inhibited flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that flagellin is an essential determinant of liver injury and demonstrated that the over-activation of TLR5 signaling by high-dose flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of flagellin-induced liver injury.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

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“…In recent years, an increasing number of studies have demonstrated the effectiveness of membrane-anchored flagellin as a mucosal adjuvant, as well as its ability to promote cytokine expression by innate immune cells and trigger the generalized recruitment of T-and B-lymphocytes to secondary lymphoid organs (Mizel & Bates, 2010). For instance, overexpression of flagella has been shown to enhance the induction of an antigen-specific immune response in macrophages and vaccination with a live attenuated strain of S. Typhimurium that produces two flagellin proteins (FliC and FljB) induced protective immune responses against oral challenge with virulent S. Typhimurium (Eom et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mouse models for assessing the cross-protective efficacy of oral non-typhoidal Salmonella vaccine candidates harbouring in-frame deletions of the ATP-dependent protease lon and other genes

Matsui

Fukiya

Kodama-Akaboshi

et al. 2015

Journal of Medical Microbiology

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In BALB/c mouse models of Salmonella enterica serovar Typhimurium infection, a single oral immunization with a mutant strain with an insertion of the chloramphenicol resistance gene into the ATP-dependent protease clpP or lon gene decreased the number of salmonellae in each tissue sample 5 days after oral challenge with virulent S. Typhimurium at weeks 26 and 54 postimmunization. These data suggested that an oral immunization with the ClpP-or Lon-disrupted S. Typhimurium strain could provide long-term protection against oral challenge with virulent S. Typhimurium. Accordingly, recombinant oral non-typhoidal Salmonella (NTS) vaccines were constructed by incorporating mutants of both S. Typhimurium and S. enterica serovar Enteritidis harbouring stable in-frame markerless deletions of the clpP-lon-sulA (suppressor of lon), lonsulA or lon-msbB (acyltransferase) genes. Amongst these orally administered vaccine candidates, those with the lon-sulA gene deletion mutants of S. Typhimurium and S. Enteritidis protected BALB/c and C57BL/6J mice against oral challenge with both virulent S. Typhimurium and virulent S. Enteritidis. Therefore, the in-frame markerless lon-sulA gene deletion mutant of S. Typhimurium or S. Enteritidis could be a promising cross-protective NTS live vaccine candidate for practical use in humans.

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“…The endotoxin value of the purified recombinant flagellin preparation was ,0.03 EU/mg. Any contamination with other PAMPs was assessed using the purified proteins to stimulate the flagellinnonresponsive RAW264.7 cells 25,26 overnight at the concentration of 4000 nM.…”

Section: Animalsmentioning

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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Flagellin as an Adjuvant: Cellular Mechanisms and Potential

Cited by 341 publications

References 76 publications

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Mouse models for assessing the cross-protective efficacy of oral non-typhoidal Salmonella vaccine candidates harbouring in-frame deletions of the ATP-dependent protease lon and other genes

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

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