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A Rapid Caspase-11 Response Induced by IFNγ Priming Is Independent of Guanylate Binding Proteins

Sky W Brubaker1, Susan M Brewer1, Liliana M Massis1

  • 1Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Iscience
|October 22, 2020
PubMed

Insights

Interferon-gamma (IFNγ) priming significantly amplifies macrophage responses to bacterial lipopolysaccharides (LPS) via caspase-11, revealing a potential unknown regulator in pyroptosis.

Area of Science:

  • Immunology
  • Cellular Biology
  • Microbiology

Background:

  • Inflammatory caspases, including murine caspase-11, detect Gram-negative bacterial invasion by binding lipopolysaccharides (LPS).
  • Caspase-11 activation leads to pyroptotic cell death and sepsis pathogenesis.
  • Extracellular priming factors can enhance caspase-11-dependent pyroptosis.

Purpose of the Study:

  • To compare different priming agents for their effects on macrophage response to cytosolic LPS.
  • To investigate the mechanisms underlying IFNγ-primed enhancement of caspase-11-dependent pyroptosis.

Main Methods:

  • Comparison of various priming agents on macrophage responses to cytosolic LPS.
  • Assessment of pyroptosis levels in macrophages with stable caspase-11 expression and in those lacking guanylate-binding proteins (GBPs).
  • Analysis of IFNγ's effect on caspase-11 and GBP expression.

Main Results:

  • IFNγ priming elicits the most rapid and amplified macrophage response to cytosolic LPS compared to other agents.
  • IFNγ-induced expression of caspase-11 and GBPs does not fully explain the enhanced pyroptosis.
  • IFNγ priming increased pyroptosis in response to cytosolic LPS even in macrophages lacking chromosome 3-encoded GBPs.

Conclusions:

  • IFNγ is a potent priming agent for enhancing macrophage pyroptosis in response to cytosolic LPS.
  • The enhanced response is not solely attributable to increased caspase-11 and GBP expression.
  • An unknown regulator, upregulated by IFNγ, likely plays a crucial role in caspase-11-dependent pyroptosis.
Keywords:
Cell BiologyImmunology

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