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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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Evaluation of Caspase Activation to Assess Innate Immune Cell Death

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ASC/PYCARD and caspase-1 regulate the IL-18/IFN-gamma axis during Anaplasma phagocytophilum infection

Joao H F Pedra1, Fayyaz S Sutterwala, Bindu Sukumaran

  • 1Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|September 20, 2007
PubMed

Insights

The apoptotic specklike protein with a caspase-activating recruiting domain (ASC) and caspase-1 are crucial for controlling Anaplasma phagocytophilum infection by regulating interleukin-18 (IL-18) and interferon-gamma (IFN-gamma) production.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Cellular Biology

Background:

  • Anaplasma phagocytophilum is an intracellular pathogen causing severe illness.
  • Interferon-gamma (IFN-gamma) is vital for controlling A. phagocytophilum, but its regulation is not fully understood.
  • Nod-like receptor (NLR) pathways are involved in immune responses.

Purpose of the Study:

  • To investigate the role of apoptotic specklike protein with a caspase-activating recruiting domain (ASC) in regulating IFN-gamma production during A. phagocytophilum infection.
  • To elucidate the mechanisms by which ASC and caspase-1 influence the IL-18/IFN-gamma axis.

Main Methods:

  • Utilized caspase-1- and asc-null mouse models to assess susceptibility to A. phagocytophilum infection.
  • Measured IL-18 and IFN-gamma levels in peripheral blood.
  • Assessed CD4+ T cell-mediated IFN-gamma production in vitro after restimulation with A. phagocytophilum.
  • Investigated the involvement of NLR family members IPAF/NLRC4 and NALP3/NLRP3.

Main Results:

  • Caspase-1- and ASC-deficient mice exhibited increased susceptibility to A. phagocytophilum infection.
  • Absence of IL-18 secretion and reduced IFN-gamma levels were observed in deficient mice.
  • ASC and caspase-1 deficiency impaired CD4+ T cell-mediated IFN-gamma production.
  • IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-gamma production.

Conclusions:

  • ASC and caspase-1 are essential for the IL-18/IFN-gamma axis regulation during A. phagocytophilum infection.
  • These molecules are critical for IFN-gamma-mediated control of A. phagocytophilum.
  • The findings highlight a novel mechanism in the innate immune response to bacterial pathogens.

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