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Forward Genetics Screens Using Macrophages to Identify Toxoplasma gondii Genes Important for Resistance to IFN-γ-Dependent Cell Autonomous Immunity
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Mouse neutrophils require JNK2 MAPK for Toxoplasma gondii-induced IL-12p40 and CCL2/MCP-1 release

Woraporn Sukhumavasi1, Charlotte E Egan, Eric Y Denkers

  • 1Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|September 6, 2007
PubMed

Insights

Mouse neutrophils show low JNK1 but functional JNK2, which is activated by Toxoplasma gondii. JNK2 is essential for producing IL-12p40 and CCL2/MCP-1 in neutrophils during infection.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The c-Jun N-terminal kinase (JNK)/stress-activated MAPK (SAPK) pathway regulates inflammatory responses and cytokine production, including IL-12.
  • JNK1 and JNK2 isoforms are broadly expressed, while JNK3 is restricted to specific tissues.
  • JNK/SAPK signaling in neutrophils remains understudied.

Purpose of the Study:

  • To investigate JNK/SAPK expression and activity patterns in mouse neutrophils.
  • To determine the role of JNK2 in neutrophil responses to the protozoan parasite Toxoplasma gondii.

Main Methods:

  • Western blot analysis to assess JNK/SAPK expression in wild-type and JNK2 knockout (JNK2-/-) neutrophils.
  • Infection of neutrophils with Toxoplasma gondii to evaluate JNK2 activation.
  • Flow cytometry (FACS) for intracellular staining and analysis of neutrophil activation.
  • Assessment of neutrophil functions including cytokine production (IL-12p40, CCL2/MCP-1), chemotaxis, phagocytosis, and oxidative burst activity in JNK2-/- neutrophils.

Main Results:

  • Neutrophils exhibited significantly lower JNK1 expression compared to macrophages, with JNK1 levels decreasing during neutrophil maturation.
  • Toxoplasma gondii infection induced rapid JNK2 phosphorylation, with preferential activation observed in infected neutrophils.
  • JNK2 was indispensable for the production of IL-12p40 and CCL2/MCP-1 by neutrophils in response to Toxoplasma gondii.
  • Neutrophil chemotaxis showed minor JNK2 dependence, while phagocytosis and oxidative burst activity were not affected by JNK2 deficiency.

Conclusions:

  • Mouse neutrophils display a unique JNK expression profile with limited JNK1 and functional JNK2.
  • Neutrophil JNK2 is activated upon invasion by Toxoplasma gondii.
  • JNK2 plays a critical role in mediating neutrophil production of key inflammatory cytokines IL-12p40 and CCL2/MCP-1 during microbial pathogen challenge.

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