Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

Christopher T Turner1, Matthew R Zeglinski1, Katlyn C Richardson1

  • 1International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Insights

Granzyme K (GzmK) promotes inflammation and impairs skin healing after burns. Removing GzmK improved wound closure and tissue repair in mice, highlighting its role in thermal injury inflammation.

Area of Science:

  • Immunology
  • Dermatology
  • Protease research

Background:

  • Granzyme K (GzmK), a serine protease, is linked to inflammation and elevated in sepsis.
  • Its role in thermal injury and wound healing is not well understood.

Purpose of the Study:

  • To investigate the role of Granzyme K (GzmK) in inflammation and tissue remodeling following thermal injury.
  • To determine GzmK's impact on skin wound healing and epithelialization.

Main Methods:

  • Analyzing GzmK expression in human burn tissue and cultured macrophages.
  • Utilizing wild-type and GzmK knockout (GzmK-/-) mice subjected to thermal injury.
  • Assessing wound closure, matrix organization, tensile strength, and inflammatory markers (IL-6, ICAM-1, VCAM-1, MCP-1).
  • Investigating GzmK's effect on keratinocytes and fibroblasts in vitro.

Main Results:

  • GzmK was elevated in human burn tissue, primarily in macrophages.
  • GzmK knockout mice showed enhanced wound healing, improved matrix organization, and increased tensile strength.
  • Reduced levels of key inflammatory markers were observed in GzmK knockout mice.
  • GzmK induced IL-6 expression in keratinocytes and fibroblasts, dependent on PAR-1 activation.
  • GzmK impaired in vitro keratinocyte wound healing, suggesting sensitivity to its proteolysis.

Conclusions:

  • Granzyme K (GzmK) significantly contributes to inflammation and impedes epithelialization during thermal wound healing.
  • Targeting GzmK may offer a therapeutic strategy to improve skin wound repair.

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