Regulation of the Differentiation and Function of Alternatively Activated Macrophages
Date
2015-09-11
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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,
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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.
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Keywords
Microbiology, Physiology
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