Systemic sclerosis (SSc), or scleroderma, is a complex, rare disease of unknown etiology. Macrophages constitute a large portion of the immune cell infiltrate in the skin of patients with SSc, and are an important target of study. Particularly, the M2 macrophage has been implicated scleroderma and other fibrotic diseases as a key contributor to fibrotic processes. However, the definition of an M2 macrophage appears to change with context, and is poorly elucidated in different species. With varying characterizations between species and disease models, there is a need to establish some consensus on how to identify this macrophage in an uniform manner across species. We used a bioinformatic approach to identify a unique gene signature for the M2 macrophage phenotype, which is shared between human and mouse systems. We were able to confirm a 7-gene subset of this theorized signature using human and mouse in vitro systems. In addition, we selected one of the identified genes, Clec7a, and characterized its expression at the protein level on different macrophage phenotypes, across several human and mouse models. Our data show that Clec7a is a more selective marker of murine M2 macrophages than current reference markers, and is useful in human models as well. Using our M2-specific gene signature, we also identified a potential inhibitor of the signature and showed its effects on M2 marker expression. Finally, we showed some preliminary work into Clec7a expression in skin tissue from patients with scleroderma. Overall, our data suggest that Clec7a may be a valuable addition to the panel of markers used to characterize M2 macrophages and distinguish between macrophage phenotypes, and perhaps provide clarity into the development and function of the M2 macrophage. Better understanding of the M2 macrophage would ultimately be useful to the study of fibrotic diseases such as scleroderma, wherein this macrophage phenotype may be a viable target for antifibrotic therapy. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/23455 |
| Date | January 2017 |
| Creators | Parthasarathy, Pavithra |
| Contributors | Ask, Kjetil, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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