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Pyrin critical to macrophage IL-1beta response to Francisella challenge

Mikhail A Gavrilin1, Srabani Mitra, Sudarshan Seshadri

  • 1Division of Pulmonary Allergy Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA. gavrilin.1@osu.edu

Journal of Immunology (Baltimore, Md. : 1950)
|June 5, 2009
PubMed

Insights

Human macrophages struggle to release IL-1beta compared to monocytes. This study reveals that intracellular pyrin levels are crucial for IL-1beta release, impacting immune responses to bacterial infections.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Human macrophages exhibit impaired processing and release of Interleukin-1 beta (IL-1beta) compared to monocytes.
  • Understanding this difference is key to comprehending innate immune responses.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the differential IL-1beta release between human monocytes and monocyte-derived macrophages (MDM).
  • To determine the role of pyrin (MEFV) in regulating IL-1beta processing and release.

Main Methods:

  • Comparative analysis of IL-1beta release in monocytes and MDM challenged with *Francisella novicida*.
  • Gene expression profiling and immunoblotting to assess pyrin levels.
  • Pyrin knockdown using small interfering RNA (siRNA) in monocytes and THP-1 cells.
  • Restoration of pyrin levels via M-CSF treatment in MDM and stable pyrin expression in THP-1 derived macrophages.

Main Results:

  • Both monocytes and MDM produced similar levels of IL-1beta mRNA and pro-IL-1beta, but only monocytes efficiently released mature IL-1beta.
  • MDM showed significantly lower expression of pyrin mRNA and protein compared to monocytes.
  • Pyrin knockdown in monocytes and THP-1 cells markedly reduced IL-1beta release.
  • M-CSF treatment restored pyrin levels and IL-1beta release in MDM.
  • Stable pyrin expression in THP-1 macrophages enhanced caspase-1 activation and IL-1beta release upon *F. novicida* infection.

Conclusions:

  • Intracellular pyrin levels are a critical positive regulator of IL-1beta responsiveness in macrophages during *Francisella* infection.
  • The deficiency in pyrin expression contributes to the impaired IL-1beta release observed in human macrophages relative to monocytes.

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