Murine leupaxin deletion results in spontaneous weight gain, tissue inflammation, and integrin signaling defects

• Author / Creator

  Liu, JiaQi

• Immune cells are remarkable in their ability to gracefully travel throughout the body to maintain homeostasis and defend against pathogens. Key proteins during immune cell migration are the integrin proteins that bind to specific ligands for robust adherence of the leukocyte to the substrate. Integrin engagement allows for downstream signaling instructing the cell to reorganize its cytoskeleton and initiate morphological changes that occur during migration across the endothelial barrier. However, another less well studied function of integrins is its ability to signal for cell polarization during cytotoxic lymphocyte directed granule release. Primarily in natural killer (NK) cells, LFA-1 outside-in signaling orchestrates cellular polarization that moves the microtubule organizing center (MTOC) and lytic granules towards the intended target cell.
  My research is to study the effects of leupaxin knockout on the individual NK cell and the leukocyte populations of the spleen, visceral adipose tissue, and liver of the mice. Leupaxin belongs to the paxillin family of proteins and is a cytoskeletal protein downstream of integrin signaling preferentially expressed in cells of hematopoietic origin. I found that leupaxin deletion reduced the granule polarization towards the MTOC during target cell killing by the NK cell but did not impede the NK cell cytotoxicity and degranulation. During cell crawling, leupaxin knockout NK cells have faster velocity on VCAM-1 and fibronectin. However, leupaxin deletion did not alter the RANTES chemokine directed transwell migration of NK cells. The integrin downstream signaling functionality of leupaxin may act as a fine-tuning mechanism to assist in granule polarization and reduce integrin protein turnover during cell crawling.
  Overall, leupaxin knockout mice display altered metabolic activity as they have increased body weight compared to their wildtype (WT) counterparts. Sex differences can be observed in the leupaxin knockout mice as females have onset of increased weight gain at an earlier age along with significant weight differences in liver and visceral adipose tissue. Leupaxin knockout mice did not
  ii
  have alterations to their splenic populations. Alterations in the CD44 by CD62L profile towards effector memory T cell subsets can be observed within the CD8 T cells of the visceral adipose tissue (VAT) and liver of both sexes. Innate immune cells display an increase in VAT macrophage population frequency and liver resident NK cell population frequency suggesting a possible onset of obesity related low-grade inflammatory condition. These results suggest that the leupaxin integrin signaling network is pivotal to the prevention of steady state activation of T cells.

• Subjects / Keywords

  • Leupaxin
  • NK cell
  • Integrin

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-6gfy-s283

• License

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