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Mechanobiology of Leukocyte Adhesion

Benson, Bryan Lauck
http://orcid.org/0000-0003-4318-5693
http://rave.ohiolink.edu/etdc/view?acc_num=case1537210425881461

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Pathology.
Splitting their lives between the chaotic, dynamic environment within the bloodstream and the calm, stable waters of tissues, leukocytes face unique challenges in integrating and responding to mechanical forces across their lifespan. The bloodstream affords leukocytes rapid transit. In order to be useful, leukocytes must exit from the bloodstream and enter lymphoid organs for antigen surveillance or sites of inflammation to respond to threats. This process, extravasation via the leukocyte adhesion cascade, consists of at least 8 steps and each involves dynamic interactions with plasma, erythrocytes, platelets, other leukocytes, endothelial cells, and cells of the tissue parenchyma. To navigate this process, leukocytes make use of an array of signaling, cytoskeletal, motor, and adhesion molecules, and emergent in the literature is the understanding that each of these has different functions in different contexts: intravascular vs. extravascular, in different tissues, and in different leukocyte subsets. Of these, by far the most important are the integrins, which bind to adhesion molecules on endothelia and are critically involved in every step of the cascade. Blockade of integrins with the monoclonal antibodies natalizumab and efalizumab results in almost complete ablation of leukocyte transmigration into tissue and marked clinical benefit in autoimmune diseases, but also carries risks of rare but potentially fatal progressive multifocal leukencephalopathy. The focus of the present work is on understanding the responses of leukocytes to physical forces in the adhesion cascade, with emphasis on shear stress, erythrocyte collisions, and leukocyte cytoskeleton-coupled motor protein activity. We first generated biomimetic in vitro models of the post-capillary venule, the anatomical site of leukocyte adhesion. These models afforded us the experimental control needed to demonstrate three insights. First, chemokines and cytokines cannot spread laterally within the convective context of the bloodstream, and therefore inflammation must be propagated by extravascular means. Second, collisions with erythrocytes are the most significant forces acting on leukocytes in post-capillary venules, and are essential for efficient adhesion. Finally, the mechanosensitive ion channel PIEZO1 is necessary for a feedback loop that transduces myosin activity and allows coordinated release of high affinity integrin bonds during leukocyte intravascular crawling.
Alex Huang, MD, PhD (Advisor)
Richard Ransohoff, MD (Advisor)
George Dubyak, PhD (Committee Chair)
Justin Lathia, PhD (Committee Member)
Umut Gurkan, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
174 p.
Biology; Biophysics; Immunology; Medicine; Pathology; Physiology
microfluidic; leukocyte adhesion; integrin; piezo1; lymphocyte; crawling; transmigration; chemokine

Recommended Citations

Citations

  • Benson, B. L. (2019). Mechanobiology of Leukocyte Adhesion [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1537210425881461

    APA Style (7th edition)

  • Benson, Bryan. Mechanobiology of Leukocyte Adhesion. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1537210425881461.

    MLA Style (8th edition)

  • Benson, Bryan. "Mechanobiology of Leukocyte Adhesion." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1537210425881461

    Chicago Manual of Style (17th edition)

case1537210425881461
681
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.