The TLR4-TRIF pathway can protect against the development of experimental allergic asthma

Immunology. 2017 Sep;152(1):138-149. doi: 10.1111/imm.12755. Epub 2017 Jun 20.

Abstract

The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif-/- or Myd88-/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4+ ICOS+ T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ ICOS+ cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ ICOS+ T-cell responses may be a contributing mechanism.

Keywords: Asthma; T helper type 2; Toll, interleukin-1R and resistance protein (TIR) domain-containing adaptor inducing interferon-β; Toll-like receptor 4; inducible co-stimulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / immunology
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Adoptive Transfer
  • Animals
  • Antigens, Plant / immunology
  • Asthma / immunology
  • Asthma / metabolism
  • Asthma / physiopathology
  • Asthma / prevention & control*
  • Betula / immunology
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / metabolism
  • Bronchial Hyperreactivity / physiopathology
  • Bronchial Hyperreactivity / prevention & control
  • Bronchoconstriction
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / transplantation
  • Cell Proliferation
  • Chemotaxis, Leukocyte
  • Cysteine Endopeptidases / immunology
  • Disease Models, Animal
  • Drug Combinations
  • Female
  • Genetic Predisposition to Disease
  • Inducible T-Cell Co-Stimulator Protein / immunology
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Lipopolysaccharides / immunology
  • Lung / immunology
  • Lung / metabolism*
  • Lung / physiopathology
  • Lymphocyte Activation
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Phenotype
  • Pollen / immunology
  • Rhinitis, Allergic, Seasonal / immunology
  • Rhinitis, Allergic, Seasonal / metabolism
  • Rhinitis, Allergic, Seasonal / physiopathology
  • Rhinitis, Allergic, Seasonal / prevention & control*
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Antigens, Plant
  • Drug Combinations
  • Inducible T-Cell Co-Stimulator Protein
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Protollin
  • TICAM-1 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Cysteine Endopeptidases