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Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
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The protein kinase R modifies gut physiology to limit colitis

Howard Chi Ho Yim1,2, Arindam Chakrabarti3, Sean Kessler4

  • 1Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.

Frontiers in Immunology
|March 6, 2023
PubMed

Insights

Protein kinase R (PKR) plays a dual role in gut inflammation, offering protection through its kinase activity but increasing susceptibility to injury via kinase-independent pathways. PKR influences gut physiology, microbiota, and immune homeostasis.

Area of Science:

  • Immunology
  • Gastroenterology
  • Molecular Biology

Background:

  • The innate immune system plays a crucial role in maintaining intestinal homeostasis.
  • Protein kinase R (PKR) is an innate immune molecule with known roles in viral response and apoptosis.
  • Its specific function in intestinal inflammation and gut physiology remains largely unexplored.

Purpose of the Study:

  • To investigate the role of protein kinase R (PKR) in the context of intestinal inflammation.
  • To differentiate between kinase-dependent and kinase-independent functions of PKR in a model of colitis.
  • To elucidate the mechanisms by which PKR influences gut physiology and immune homeostasis.

Main Methods:

  • Utilized dextran sulfate sodium (DSS) to induce colitis in wild-type and PKR-mutant mouse models (kinase-dead and knockout).
  • Assessed physiological responses including weight loss and inflammatory markers.
  • Analyzed goblet cell function and gut microbiota composition at homeostasis.
  • Investigated the impact of PKR on autophagy and inflammasome activity.

Main Results:

  • PKR exhibited both protective (kinase-dependent) and detrimental (kinase-independent) effects on DSS-induced colitis.
  • Kinase-dependent protection was observed against weight loss and inflammation.
  • Kinase-independent pathways increased susceptibility to DSS-induced injury.
  • PKR modulated goblet cell function and altered gut microbiota composition.
  • PKR influenced autophagy, suppressing inflammasome activity at homeostasis.

Conclusions:

  • PKR functions as a critical regulator of intestinal immune homeostasis.
  • Its dual role as a kinase and signaling molecule impacts gut physiology and susceptibility to inflammation.
  • Findings highlight PKR as a potential therapeutic target for inflammatory bowel diseases.
Keywords:
autophagycolitisgoblet cellsgut barrierinflammasomesinflammationprotein kinase

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