Examination of the Regulation of Phosphorylation Events in Macrophage Adhesion and Response to Zymosan

• Author / Creator

  St-Pierre, Joëlle

• Macrophages play a central role in innate immunity, most notably in tissue repair, phagocytosis of dead or infected cells, secretion of chemokine and cytokines at sites of infection, as well as the activation of other immune cells. These roles are highly dependent on their capacity to migrate throughout the body by mediating intercellular adhesion and adhesion to the ECM. A comprehensive understanding of the molecular mechanisms of adhesion and motility of macrophages is thus critical to better manipulate the innate immune response. Pyk2 and paxillin are key components of the macrophage cytoskeleton. I demonstrated that Pyk2 is found as two biochemically and spatially distinct populations in macrophages, based on their binding partners, serine/threonine phosphorylation status, and post-translational modifications. I further investigated the role of the protein tyrosine phosphatase CD45 on the regulation of the macrophage cytoskeleton. I found that the absence of CD45 in macrophages leads to defects in adhesion and motility; these defects are possibly due a decrease in paxillin expression. Moreover, inhibition of calpain and Pyk2 activity partially restored paxillin expression in these cells. Finally, I examined whether the absence of CD45 led to defects in macrophage responses to the yeast-derived particle zymosan. No significant differences in cytokine secretion, pathogen recognition receptor expression and rate of phagocytosis were observed in CD45-deficient macrophages. Changes in tyrosine phosphorylation and increased particle binding, however, were observed upon treatment with zymosan. In all, these results underline the contribution of Pyk2 and CD45 in the regulation of macrophage adhesion as well as the role of CD45 in the regulation of macrophage responses to fungal stimulus.

• Subjects / Keywords

  • Paxillin
  • Calpain
  • Pyk2
  • Adhesion
  • Macrophages
  • CD45

• Graduation date

  Fall 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R39W6W

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.