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

J Immunol. 2007 Oct 1;179(7):4783-91. doi: 10.4049/jimmunol.179.7.4783.

Abstract

Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within neutrophils and can cause fever, pancytopenia, or death. IFN-gamma plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN-gamma production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN-gamma axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and asc-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN-gamma levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4+ T cell-mediated IFN-gamma after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-gamma production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN-gamma-mediated control of A. phagocytophilum infection.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Anaplasma / immunology*
  • Anaplasmosis / immunology
  • Anaplasmosis / metabolism
  • Anaplasmosis / microbiology
  • Anaplasmosis / pathology
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Calcium-Binding Proteins / metabolism
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Disease Susceptibility
  • Enzyme Activation
  • HL-60 Cells
  • Humans
  • Interferon-gamma / metabolism*
  • Interleukin-18 / deficiency
  • Interleukin-18 / genetics
  • Interleukin-18 / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Th1 Cells / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Interleukin-18
  • Ipaf protein, mouse
  • Interferon-gamma
  • Caspase 1