This week we profile a recent publication in Nature Communications from
Dr. Chris Overall (third from left) at the UBC Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
Humans have over 500 different proteases, but we have only a limited understanding of the functions of a small number of these. The overall focus of my lab in the Centre for Blood Research at UBC is to understand how proteolytic processing regulates homeostasis and disease. Proteases exert control of processes by altering the functions of their substrates. My lab has developed a suite of proteomic methods (degradomics) that enable us to unravel the substrate repertoire of individual proteases as well as determine the proteolytic processing that has occurred in complex samples, for example, in diseased vs healthy tissue. By expanding our knowledge of protease function in health and disease, we hope to be able to develop new diagnostics and therapeutics that target specific proteolytic processing events.
What is the significance of the findings in this publication?
IFNγ stimulates differentiation to pro-inflammatory (M1, classically-activated) macrophages. In this publication, we demonstrate that proteolytic processing at the C-terminus of IFNγ by matrix metalloproteinase-12 (MMP-12) prevents IFNγ signaling. Systemic lupus erythematosus (SLE) patients have decreased MMP-12 expression compared with healthy controls, and in murine models of lupus and arthritis, mice with deleted or inhibited MMP-12 have worse disease. Thus, MMP-12 processing of IFNγ turns off M1 macrophage differentiation and facilitates the switch to M2 (healing, alternatively-activated) macrophages. In the absence of MMP-12, pro-inflammatory macrophages persist and contribute to chronic and autoimmune disease.
What are the next steps for this research?
Next we want to analyse MMP-12 activity levels in a larger cohort of patients with active SLE, and in patients with other IFNγ-driven inflammatory diseases. If levels of MMP-12 are reduced, then we will investigate ways to augment MMP-12 expression to restore the balance between M1 and M2 macrophages.
This research was funded by:
This work was funded by Operating grants and a Foundation grant to CMO from the Canadian Institutes of Health Research.
