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

Cell Mol Immunol. 2016 Jul;13(4):514-23. doi: 10.1038/cmi.2015.33. Epub 2015 Apr 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / drug effects*
  • Antibody Formation / immunology
  • Antibody Specificity / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cell Death / drug effects
  • Down-Regulation / drug effects*
  • Female
  • Flagellin / pharmacology*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred BALB C
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Toll-Like Receptor 5 / metabolism*


  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Interleukin-18
  • Interleukin-1beta
  • Ipaf protein, mouse
  • Recombinant Proteins
  • Toll-Like Receptor 5
  • Flagellin