Regulation of the Differentiation and Function of Alternatively Activated Macrophages
| atmire.migration.oldid | 3544 | |
| dc.contributor.advisor | McKay, Derek Mark | |
| dc.contributor.author | Fernando, Maria Ruweka | |
| dc.date.accessioned | 2015-09-11T17:14:46Z | |
| dc.date.available | 2015-11-20T08:00:39Z | |
| dc.date.issued | 2015-09-11 | |
| dc.date.submitted | 2015 | en |
| dc.description.abstract | Macrophages are important innate immune cells that are associated with two distinct polarization paradigms: a pro-inflammatory subset that is linked with bacterial killing, known as a classically activated macrophage (CAM), and an anti-inflammatory subset linked to wound healing and tissue repair, known as an alternatively activated macrophage (AAM). Even following differentiation into these specific subsets, the ability of a macrophage to adapt to a changing environment is critical for the maintenance of host homeostasis. In this thesis we have investigated the effect of myofibroblasts, a cell type that is needed for wound healing, and the microbial-derived metabolite, butyrate on the development and function of alternatively activated macrophages. In the presence of myofibroblast-derived mediators, AAM polarization was enhanced, based on increased expression of hallmark AAM markers, Arg1, Ym1 and RELMĪ±. In addition, nitric oxide production in response to LPS was suppressed. Using a reductionist in vitro coculture approach, we found that myofibroblast-derived IL-6, PGE2 and PGD2 were responsible for the observed effect. AAMs enhanced by myofibroblast-derived products were shown to be able to feed back onto the myofibroblast to limit prostaglandin production, elucidating a pathway of bi-directional communication between the two cells. We have also shown that in the presence of butyrate, AAM polarization was suppressed, via histone deacetylase inhibition. AAMs differentiated in the presence of butyrate were functionally distinct from AAMs, and displayed enhanced bacterial killing and uptake, but also suppressed Foxp3 induction in regulatory T cells. Taken together, these studies highlight the importance of the microenvironment on macrophage function and phenotype. In addition, our results showing that IL-6 and COX-2, ii i molecules often considered pro-inflammatory can enhance the development of an antiinflammatory macrophage, while butyrate, often considered to be anti-inflammatory has the opposite effect, reveal the importance of not dogmatically and definitively classifying compounds as pro- or anti-inflammatory. | en_US |
| dc.identifier.citation | Fernando, M. R. (2015). Regulation of the Differentiation and Function of Alternatively Activated Macrophages (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27590 | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/27590 | |
| dc.identifier.uri | http://hdl.handle.net/11023/2448 | |
| dc.language.iso | eng | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | en |
| dc.publisher.place | Calgary | en |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | |
| dc.subject | Microbiology | |
| dc.subject | Physiology | |
| dc.subject.classification | Macrophages | en_US |
| dc.subject.classification | Prostaglandins | en_US |
| dc.subject.classification | Butyrate | en_US |
| dc.title | Regulation of the Differentiation and Function of Alternatively Activated Macrophages | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Gastrointestinal Sciences | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.item.requestcopy | true |