The alarmin Mrp8/14 as regulator of the adaptive immune response during allergic contact dermatitis

EMBO J. 2013 Jan 9;32(1):100-11. doi: 10.1038/emboj.2012.309. Epub 2012 Nov 27.

Abstract

Mrp8 and Mrp14 are endogenous alarmins amplifying inflammation via Toll-like receptor-4 (TLR-4) activation. Due to their pro-inflammatory properties, alarmins are supposed to enhance adaptive immunity via activation of dendritic cells (DCs). In contrast, analysing a model of allergic contact dermatitis (ACD) we observed a more severe disease outcome in Mrp8/14-deficient compared to wild-type mice. This unexpected phenotype was associated with an enhanced T-cell response due to an accelerated maturation of DCs in Mrp8/14-deficient mice. Accordingly, Mrp8, the active component of the heterocomplex, inhibits early DC maturation and antigen presentation in a TLR-4-dependent manner. Transfer of DCs purified from the local lymph nodes of sensitized Mrp8/14-deficient to wild-type mice determined the outcome of ACD. Our results link a pro-inflammatory role of the endogenous TLR-4 ligand Mrp8/14 to a regulatory function in adaptive immunity, which shows some similarities with the 'hygiene hypothesis' regarding continuous TLR-4 stimulation and decreased risk of allergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antigen Presentation
  • Calgranulin A / blood
  • Calgranulin A / genetics
  • Calgranulin A / immunology
  • Calgranulin A / metabolism*
  • Calgranulin B / blood
  • Calgranulin B / genetics
  • Calgranulin B / immunology
  • Calgranulin B / metabolism*
  • Cell Communication
  • Cell Differentiation
  • Cell Proliferation
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dermatitis, Allergic Contact / immunology*
  • Dermatitis, Allergic Contact / metabolism
  • Ear / pathology
  • Leukocyte L1 Antigen Complex / immunology*
  • Leukocyte L1 Antigen Complex / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Time-Lapse Imaging
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Calgranulin A
  • Calgranulin B
  • Cytokines
  • Leukocyte L1 Antigen Complex
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4