title: Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts.
abstract: Leukocytes normally marginate toward the vascular wall in large vessels and within the microvasculature. Reversal of this process, leukocyte demargination, leads to substantial increases in the clinical white blood cell and granulocyte count and is a well-documented effect of glucocorticoid and catecholamine hormones, although the underlying mechanisms remain unclear. Here we show that alterations in granulocyte mechanical properties are the driving force behind glucocorticoid- and catecholamine-induced demargination. First, we found that the proportions of granulocytes from healthy human subjects that traversed and demarginated from microfluidic models of capillary beds and veins, respectively, increased after the subjects ingested glucocorticoids. Also, we show that glucocorticoid and catecholamine exposure reorganizes cellular cortical actin, significantly reducing granulocyte stiffness, as measured with atomic force microscopy. Furthermore, using simple kinetic theory computational modeling, we found that this reduction in stiffness alone is sufficient to cause granulocyte demargination. Taken together, our findings reveal a biomechanical answer to an old hematologic question regarding how glucocorticoids and catecholamines cause leukocyte demargination. In addition, in a broader sense, we have discovered a temporally and energetically efficient mechanism in which the innate immune system can simply alter leukocyte stiffness to fine tune margination/demargination and therefore leukocyte trafficking in general. These observations have broad clinically relevant implications for the inflammatory process overall as well as hematopoietic stem cell mobilization and homing.
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Meredith E
authors: ME
authors: Fay
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: David R
authors: DR
authors: Myers
authors: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706;
authors: Amit
authors: A
authors: Kumar
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Cory T
authors: CT
authors: Turbyfield
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Rebecca
authors: R
authors: Byler
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Kaci
authors: K
authors: Crawford
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Robert G
authors: RG
authors: Mannino
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Alvin
authors: A
authors: Laohapant
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Erika A
authors: EA
authors: Tyburski
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Yumiko
authors: Y
authors: Sakurai
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Michael J
authors: MJ
authors: Rosenbluth
authors: Physics Faculty, The Evergreen State College, Olympia, WA 98505.
authors: Neil A
authors: NA
authors: Switz
authors: George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
authors: Todd A
authors: TA
authors: Sulchek
authors: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706;
authors: Michael D
authors: http://orcid.org/0000-0003-4983-4949
authors: MD
authors: Graham
authors: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322; Winship Cancer Institute, Emory University, Atlanta, GA 30322; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332; wilbur.lam@emory.edu.
authors: Wilbur A
authors: WA
authors: Lam
mesh_terms: D002395:Catecholamines / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D056656:Lab-On-A-Chip Devices; D007958:Leukocyte Count / Q000295:instrumentation / Q000379:methods; D008297:Male; D008955:Models, Cardiovascular
chemical_list: D002395:Catecholamines; D005938:Glucocorticoids
keywords: atomic force microscopy; cellular mechanics; demargination; leukocyte deformability; microfluidics