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Flagellin: a unique microbe-associated molecular pattern and a multi-faceted immunomodulator

Cellular & Molecular Immunology volume 14, pages 862–864 (2017)Cite this article

Mammals peacefully co-exist with vast numbers of different bacteria most of the time. Whether pathogenic, nonpathogenic or commensal to a mammalian host, bacteria produce microbe-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs) that are recognized by multiple classes of germline-encoded pattern-recognition receptors (PRRs). Flagellin, a major structural protein of bacterial flagella, is composed of four domains (D0, D1, D2 and D3), of which the D0 and D1 domains are the most highly conserved. As a MAMP derived from bacteria, flagellin is dually recognized by Toll-like receptor 5 (TLR5) in the extracellular space and by NLR neuronal apoptosis inhibitory protein 5 (NAIP5) and NAIP6 in the cytosol.1, 2 TLR5 detects flagellin by binding specifically to its highly conserved domain D1, whereas NAIP5 or NAIP6 detects intracellular flagellin by specific binding to its C-terminus via 35 amino acids in the D0 domain. Flagellin-activated TLR5 triggers proinflammatory genes, including IL-6, TNF-α, and KC, whereas flagellin-activated NAIP5/6 promotes the assembly of the NLRC4 inflammasome, activation of caspase 1, secretion of IL-1β/IL-18 and pyroptosis of infected cells.1

As an evolutionarily conserved and vital element for mobile bacteria regardless of pathogenic, nonpathogenic or commensal characteristics, flagellin can be recognized by TLR5 on the cell surface and/or detected by cytosolic receptor NAIP5 or NAIP6 inside cell. The recognition and response profile of flagellin by the innate immune system is possibly location dependent (extracellular or intracellular), type dependent (amino acid sequence of flagellin) and quantity dependent (amount of flagellin molecule). The dual sensor strategy implies that the immune system can recognize flagellated pathogens and initiate responses based not only on whether MAMPs are presented but also on where those MAMPs are presented.7 The stronger and weaker response strategy implies that the immune system can also recognize flagellated bacteria and initiate responses based on the bacterial genome, which determines the relationship between host and microbe.4 Whether a threshold value is defined by the immune system for recognition and response to flagellin, either for TLR5 or NAIP5, remains unclear. In this respect, we may conceive different combinations of immune responses to flagellin: only TLR5 activated, only NAIP5 activated, both TLR5 and NAIP5 activated, stronger TLR5 activated and stronger NAIP5 activated. Thus, a complex cross-talk between the dual sensor TLR5 and NAIP5, and the differential output must exist in the immune recognition of and response to distinct flagellins. However, the dual activities of flagellin make this molecule a very good tool for the investigation of possible cross-talk between TLR5 and NAIP5. Using this tool, we assessed the effects of flagellin and its mutants lacking the ability to activate TLR5 and NAIP5/NLRC4 alone or in combination on the adaptive immune responses against flagellin. Activation of NLRC4 in macrophage downregulates TLR5-mediated antibody immune responses (see Figure 1).8 The finding revealed an interaction between NLRC4 activation and TLR5 activation by flagellin, which affects the output of specific immune responses. Using recombinant variant flagellins, we also found that NAIP5 and NAIP6 differentially recognize flagellins (unpublished data). However, how the cross-talk and interaction between NAIP5/6 and TLR5 signaling on specific immune responses affect bacterial infections remains to be elucidated.

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References

  1. Miao EA, Andersen-Nissen E, Warren SE, Aderem A . TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol 2007; 29: 275–288.

    Article  CAS  PubMed  Google Scholar 

  2. Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011; 477: 596–600.

    Article  CAS  PubMed  Google Scholar 

  3. Kamada N, Chen GY, Inohara N, Nunez G . Control of pathogens and pathobionts by the gut microbiota. Nat Immunol 2013; 14: 685–690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yang J, Zhang E, Liu F, Zhang Y, Zhong M, Li Y et al. Flagellins of Salmonella Typhi and nonpathogenic Escherichia coli are differentially recognized through the NLRC4 pathway in macrophages. J Innate Immunity 2014; 6: 47–57.

    Article  CAS  Google Scholar 

  5. Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S et al. NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat Immunol 2012; 13: 449–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kayama H, Takeda K . Functions of innate immune cells and commensal bacteria in gut homeostasis. J Biochem 2016; 159: 141–149.

    Article  CAS  PubMed  Google Scholar 

  7. Vance RE, Isberg RR, Portnoy DA . Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 2009; 6: 10–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li W, Yang J, Zhang E, Zhong M, Xiao Y, Yu J et al. Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. Cell Mol Immunol 2016; 13: 514–523.

    Article  PubMed  Google Scholar 

  9. Brackett CM, Kojouharov B, Veith J, Greene KF, Burdelya LG, Gollnick SO et al. Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis. Proc Natl Acad Sci USA 2016; 113: E874–E883.

    Article  CAS  PubMed  Google Scholar 

  10. Yang H, Brackett CM, Morales-Tirado VM, Li Z, Zhang Q, Wilson MW et al. The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. Oncotarget 2016; 7: 2936–2950.

    PubMed  Google Scholar 

  11. Mizel SB, Bates JT . Flagellin as an adjuvant: cellular mechanisms and potential. J Immunol 2010; 185: 5677–5682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cao Y, Zhang E, Yang J, Yang Y, Yu J, Xiao Y et al. Frontline Science: Nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway dendritic cells and subsequent IgA response. J Leukoc Biol 2017; 102: 1–13.

    Article  Google Scholar 

  13. Bao R, Yang JY, Sun Y, Zhou DH, Yang Y, Li YM et al. Flagellin-PAc fusion protein inhibits progression of established caries. J Dent Res 2015; 94: 955–960.

    Article  CAS  PubMed  Google Scholar 

  14. Sun Y, Shi W, Yang JY, Zhou DH, Chen YQ, Zhang Y et al. Flagellin-PAc fusion protein is a high-efficacy anti-caries mucosal vaccine. J Dent Res 2012; 91: 941–947.

    Article  CAS  PubMed  Google Scholar 

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  1. Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, Hubei, China

    Maohua Zhong, Huimin Yan & Yaoming Li

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  1. Maohua Zhong
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Correspondence to Yaoming Li.

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Zhong, M., Yan, H. & Li, Y. Flagellin: a unique microbe-associated molecular pattern and a multi-faceted immunomodulator. Cell Mol Immunol 14, 862–864 (2017). https://doi.org/10.1038/cmi.2017.78

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