Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells

Shim, Jae Uoong; Lee, Shee Eun; Hwang, Wooncheol; Lee, Changhon; Park, Jung Won; Sohn, Jung Ho; Nam, Jong Hee; Kim, Young; Rhee, Joon Haeng; Im, Sin Hyeog; Koh, Young Il

doi:10.1016/j.jaci.2015.07.010

Cited by 51 publications

(45 citation statements)

References 46 publications

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“…A different study reported contradictory results, proposing that the activation of TLR5 leads to Th2‐oriented responses in mice . Further, a few studies have implicated that the effect of contact with bacterial flagellin may be dose dependent: a small amount of flagellin may promote asthma by priming allergic responses, whereas higher amounts may suppress allergic asthma …”

Section: Discussionmentioning

confidence: 99%

TLR5 rs5744174 gene polymorphism is associated with the virus etiology of infant bronchiolitis but not with post‐bronchiolitis asthma

Törmänen

Teräsjärvi

Lauhkonen

et al. 2018

Health Science Reports

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Background and aim: Bronchiolitis is a leading cause of hospitalization in infants and is associated with a risk of subsequent asthma. The innate immunity genes, such as those encoding toll-like receptors (TLRs), are likely to play a role in bronchiolitis and post-bronchiolitis outcome. Thus far, only one study has considered TLR5 genes in respiratory syncytial virus (RSV) bronchiolitis. The aim of this study was to investigate the association of TLR5 gene polymorphism with virus etiology and severity of bronchiolitis, and with post-bronchiolitis asthma.Methods: We recruited 164 infants (age < 6 months) hospitalized for bronchiolitis in this study and determined TLR5 rs5744174 (C > T) single nucleotide polymorphism, virus etiology and severity markers of bronchiolitis, and presence of post-bronchiolitis asthma until age 11 to 13 years.Results: RSV was detected in 113 (68.9%), rhinovirus in 19 (11.6%), and some other virus in 20 (12.2%) cases. Non-RSV etiology was more common among infants with the variant CT or TT genotype in the TLR5 rs5744174 gene than in those with the CC genotype (89.7% vs 71.7%, P = 0.03). TLR5 rs5744174 polymorphism was not associated with the need of supplementary oxygen or feeding support, with the length of hospital stay, or with post-bronchiolitis asthma at any age. Conclusion:The TLR5 rs5744174 variant genotype may increase the susceptibility to bronchiolitis not caused by RSV. 2This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

TLR5 rs5744174 gene polymorphism is associated with the virus etiology of infant bronchiolitis but not with post‐bronchiolitis asthma

Törmänen

Teräsjärvi

Lauhkonen

et al. 2018

Health Science Reports

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“…Although our and other studies differed somewhat in the source and endotoxin-level of flagellin, the sensitization and challenge regime, and the experimental read-outs, all our results support that global conclusion that flagellin as an adjuvant promotes a robust T H 2 responses in the lungs in B6 mice. Interestingly, a previous study found when flagellin was given in the airways of BALB/c mice after sensitization by OVA/alum or by house dust mite, flagellin inhibited the developing T H 2 response [54]. Furthermore, bone-marrow-derived DCs stimulated with an OVA-flagellin fusion protein produced IL-10 [55], and these stimulated DCs could inhibit T H 2 cytokine production in vitro [56].…”

Section: Discussionmentioning

confidence: 99%

Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9

Lee

Sinha

et al. 2016

PLoS ONE

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Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll-like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response. CpG ODN induced mRNA encoding interleukin (IL)-12 p40, whereas, flagellin caused IL-33 secretion and induced mRNAs encoding IL-1 and thymic stromal lymphopoietin (TSLP). By using mice deficient in the TLR and IL-1R signaling molecule, myeloid differentiation primary response 88 (MyD88), in conventional dendritic cells (cDCs) and alveolar macrophages (AMs), and by cell sorting different lung populations after 2 hours of in vivo stimulation, we characterized the cell types that rapidly produced inflammatory cytokines in response to TLR stimulation. CpG ODN was likely recognized by TLR9 on cDCs and AMs, which made mRNA encoding IL-12. IL-12 was necessary for the subsequent innate and adaptive interferon-γ production. In contrast, flagellin stimulated multiple cells of hematopoietic and non-hematopoietic origin, including AMs, DCs, monocytes, and lung epithelial cells. AMs were largely responsible for IL-1α, whereas lung epithelial cells made TSLP. Multiple hematopoietic cells, including AMs, DCs, and monocytes contributed to other cytokines, including IL-1β and TNFα. MyD88-dependent signals, likely through IL-1R and IL-33R, and MyD88-independent signals, likely from TSLP, were necessary in cDCs for promotion of the early IL-4 response by CD4 T cells in the draining lymph node. Thus, the cell types that responded to TLR ligands were a critical determinant of the innate cytokines produced and the character of the resulting adaptive immune response in the airways.

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“…In conclusion, flagellin is an efficient mucosal adjuvant for nasal, respiratory and oral vaccinations [41,42] Respiratory administration of flagellin was suggested to be associated with the priming of allergy [44]. However, a recent study demonstrated that flagellin downregulates allergic response [45].This discrepancy may be due to the quantity and purity of flagellin that allows the development of Tregs involved in the desensitization to allergens.…”

Section: Epithelial Responses To Flagellin At Mucosal Surfacesmentioning

confidence: 99%

Compartmentalized Antimicrobial Defenses in Response to Flagellin

Vijayan

Rumbo

Carnoy

et al. 2018

Trends in Microbiology

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Motility is often a pathogenicity determinant of bacteria targeting mucosal tissues. Flagella constitute the machinery that propels bacteria into appropriate niches. Besides motility, the structural component, flagellin, which forms the flagella, targets Toll-like receptor 5 (TLR5) to activate innate immunity. The compartmentalization of flagellin-mediated immunity and the contribution of epithelial cells and dendritic cells in detecting flagellin within luminal and basal sides are highlighted here, respectively. While a direct stimulation of the epithelium mainly results in recruitment of immune cells and production of antimicrobial molecules, TLR5 engagement on parenchymal dendritic cells can contribute to the stimulation of innate lymphocytes such as type 3 innate lymphoid cells, as well as T helper cells. This review, therefore, illustrates how the innate and adaptive immunity to flagellin are differentially regulated by the epithelium and the dendritic cells in response to pathogens that either colonize or invade mucosa.

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Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells

Cited by 51 publications

References 46 publications

TLR5 rs5744174 gene polymorphism is associated with the virus etiology of infant bronchiolitis but not with post‐bronchiolitis asthma

TLR5 rs5744174 gene polymorphism is associated with the virus etiology of infant bronchiolitis but not with post‐bronchiolitis asthma

Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9

Compartmentalized Antimicrobial Defenses in Response to Flagellin

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