The IL-36 receptor pathway regulates Aspergillus fumigatus-induced Th1 and Th17 responses

Eur J Immunol. 2013 Feb;43(2):416-26. doi: 10.1002/eji.201242711. Epub 2012 Dec 18.

Abstract

IL-1 drives Th responses, particularly Th17, in host defense. Sharing the same co-receptor, the IL-1 family member IL-36 exhibits properties similar to those of IL-1. In the present study, we investigated the role of IL-36 in Aspergillus fumigatus-induced human Th responses. We observed that different morphological forms of A. fumigatus variably increase steady-state mRNA of IL-36 subfamily members. IL-36α is not significantly induced by any morphological form of Aspergillus. Most strikingly, IL-36γ is significantly induced by live A. fumigatus conidia and heat-killed hyphae, whereas IL-36Ra (IL-36 receptor antagonist) is significantly induced by heat-killed conidia, hyphae, and live conidia. We also observed that IL-36γ expression is dependent on the dectin-1/Syk and TLR4 signaling pathway. In contrast, TLR2 and CR3 inhibit IL-36γ expression. The biological relevance of IL-36 induction by Aspergillus is demonstrated by experiments showing that inhibition of the IL-36 receptor by IL-36Ra reduces Aspergillus-induced IL-17 and IFN-γ. These data describe that IL-36-dependent signals are a novel cytokine pathway that regulates Th responses induced by A. fumigatus, and demonstrate a role for TLR4 and dectin-1 in the induction of IL-36γ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspergillosis / genetics
  • Aspergillosis / immunology*
  • Aspergillosis / metabolism
  • Aspergillosis / microbiology
  • Aspergillus fumigatus / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Hyphae / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • Macrophage-1 Antigen / genetics
  • Macrophage-1 Antigen / immunology
  • Macrophage-1 Antigen / metabolism
  • RNA, Messenger / genetics
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Receptors, Interleukin / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Spores, Fungal / immunology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism

Substances

  • CLEC7A protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-17
  • Lectins, C-Type
  • Macrophage-1 Antigen
  • RNA, Messenger
  • Receptors, Interleukin
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • interleukin-36 receptor, human
  • Interferon-gamma