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Myeloid-related proteins rapidly modulate macrophage nitric oxide production during innate immune response

Philippe Pouliot1, Isabelle Plante, Marie-Astrid Raquil

  • 1Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.

Journal of Immunology (Baltimore, Md. : 1950)
|August 21, 2008
PubMed

Insights

Myeloid-related proteins (MRPs) significantly boost nitric oxide (NO) production in macrophages, enhancing microbicidal functions. This discovery highlights MRPs as key regulators of innate immunity and inflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • S100A8 and S100A9 (myeloid-related proteins, MRPs) are calcium-binding proteins secreted by myeloid cells.
  • These proteins act as extracellular, cytokine-like molecules, promoting immune cell recruitment and serving as inflammation markers.
  • Their role in modulating phagocyte microbicidal functions remained largely unexplored.

Purpose of the Study:

  • To investigate the role of MRPs in regulating microbicidal functions of macrophages.
  • To determine if MRPs influence nitric oxide (NO) production in macrophages.
  • To elucidate the signaling pathways involved in MRP-mediated macrophage activation.

Main Methods:

  • Murine macrophages (Mphi) were stimulated with MRPs.
  • Nitric oxide (NO) production was measured.
  • Inducible NO synthase (iNOS) expression (gene and protein) was assessed.
  • Phosphorylation of signaling kinases (SAPK/JNK, MEK, ERK) and NF-kappaB translocation were analyzed.
  • Synergistic effects with IFN-gamma and TLR4 dependence were investigated.

Main Results:

  • MRPs potently induced NO production in Mphi.
  • This induction correlated with increased iNOS expression at both gene and protein levels.
  • MRP stimulation led to phosphorylation of SAPK/JNK, MEK, and ERK, and rapid NF-kappaB nuclear translocation.
  • A strong synergy in NO production was observed when MRPs were combined with IFN-gamma, involving distinct signaling pathways (SAPK/JNK, ERK, NF-kappaB for MRPs; JAK/STAT for IFN-gamma).
  • The MRP-induced NO production was dependent on Toll-like receptor 4 (TLR4).

Conclusions:

  • Myeloid-related proteins (MRPs) are potent inducers of nitric oxide (NO) production in macrophages.
  • MRPs activate key signaling pathways, including SAPK/JNK, ERK, and NF-kappaB, contributing to macrophage microbicidal activity.
  • The synergistic effect with IFN-gamma suggests complex crosstalk between distinct immune signaling pathways.
  • These findings identify MRPs as crucial regulators of macrophage function and potential therapeutic targets in inflammatory diseases.

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