Drosophila Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells

EMBO J. 2011 Mar 16;30(6):1123-36. doi: 10.1038/emboj.2011.4. Epub 2011 Feb 4.

Abstract

Immune signalling pathways need to be tightly regulated as overactivation of these pathways can result in chronic inflammatory diseases and cancer. NF-κB signalling and associated innate immune pathways are crucial in the first line of defense against infection in all animals. In a genome-wide RNAi screen for modulators of Drosophila immune deficiency (IMD)/NF-κB signalling, we identified components of the Ras/MAPK pathway as essential for suppression of IMD pathway activity, even in the absence of an immune challenge. Downregulation of Ras/MAPK activity mimics the induction of innate immune responses by microbial patterns. Conversely, ectopic Ras/MAPK pathway activation results in the suppression of Drosophila IMD/NF-κB signalling. Mechanistically, we show that the Ras/MAPK pathway acts by inducing transcription of the IMD pathway inhibitor Pirk/Rudra/PIMS. Finally, in vivo experiments demonstrate a requirement for Ras/MAPK signalling in restricting innate immune responses in haemocytes, fat body and adult intestinal stem cells. Our observations provide an example of a pathway that promotes cell proliferation and has simultaneously been utilized to limit the immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / immunology
  • Drosophila Proteins / biosynthesis*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / immunology*
  • Fat Body / immunology
  • Gene Expression Regulation
  • Hemocytes / immunology
  • Immunity, Innate*
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Stem Cells / immunology
  • ras Proteins / metabolism*

Substances

  • Drosophila Proteins
  • NF-kappa B
  • imd protein, Drosophila
  • Pvr protein, Drosophila
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins