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

By November 19, 2018No Comments

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This week we profile a recent publication in the Journal of Investigative Dermatology from the
laboratory of Dr. David Granville (pictured, front) at iCORD and the UBC Centre for Heart Lung Innovation.

Can you provide a brief overview of your lab’s current research focus?

Dr. Granville’s laboratory is focused on the role of immune-secreted proteases in tissue injury, inflammation and repair in both health and disease. A major foci centres around a family of immune cell-secreted serine proteases known as Granzymes (Granule-secreted enzymes) that become elevated during inflammation and contribute to pathogenesis in conditions associated with impaired healing, loss of endothelial/epithelial barrier function, matrix degradation and loss of tissue function in autoimmune and/or age-related chronic inflammatory diseases. There are 5 Granzymes in humans: GzmA (Tryptase), GzmB (Aspase), GzmK (Tryptase), GzmH (Chymase) and GzmM (Metase). Each appears to be unique, possessing different substrate specificities, cell sources, and functions.  In collaboration with viDA Therapeutics and CDRD, Dr. Granville is developing drugs targeting Granzymes. Their lead is a topical inhibitor of GzmB that has shown efficacy in models of autoimmune blistering, scarring, impaired healing and other autoimmune conditions. They are also developing systemic GzmB inhibitors that are showing promise in cardiovascular and autoimmune neuropathy models. Dr. Granville is also in the early stages of development of inhibitors targeting other Granzymes, including GzmK.

What is the significance of the findings in this publication?

Granzyme K (GzmK) is occasionally referred to as an ‘orphan granzyme’ due to the lack of knowledge pertaining to its function in health and disease. To our knowledge, the present study, published in J. Invest. Dermatol., is the first study to ever examine the role of GzmK in any model of injury and inflammation and only documented study looking at a role for GzmK in skin. In the study, lead author Dr. Chris Turner along with Dr. Matt Zeglinski, post-doctoral fellows in Dr. David Granville’s laboratory, and other co-authors, investigated the role of GzmK in inflammation and repair in a murine model of acute cutaneous wound healing. GzmK deficiency resulted in improved wound healing as exhibited by reduced inflammation and increased wound epithelialization that led to improved remodeling and increased wound tensile strength.  Unlike GzmB, which tends to be associated with autoimmune and/or chronic inflammatory disease, GzmK appears to be involved in acute inflammation.  GzmK was found to be expressed in classically-activated M1 macrophages and promoted the released of pro-inflammatory cytokines through a PAR-1-dependent pathway.

What are the next steps for this research?

Dr. Granville’s lab is one of the only groups in the world with access to GzmK-knockout mice and other tools to study this protease. Studies are underway to determine the role of GzmK in other pro-inflammatory skin diseases and other conditions. His group has also developed a screening assay and are actively screening for inhibitors that will be tested and validated in the appropriate models.

This research was funded by:

The authors are very grateful for the funding support from MITACS, Canadian Institutes for Health Research, Michael Smith Foundation for Health Research, and the Rick Hansen Institute.

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