Recruitment of leukocytes to sites of acute inflammation is a finely orchestrated process initiated by membrane expression and functional activation of leukocyte and endothelial cell adhesion molecules (CAMs) including selectins, integrins, and Ig-super family ligands. A set of unifying themes have emerged over the tenure of this R01 which provide molecular scale insight into how PMNs integrate force as a spatio-mechanical cue in the transition from rolling to firm arrest and transendothelial migration: 1) Selectins are endowed with mechanical and biochemical properties which allow them to function as both adhesive and signal transduction receptors;2) Shear stress and transmembrane calcium release-activated Ca2+ (CRAC) channels regulate intracellular calcium flux which functions to synchronize integrin mediated arrest and cell migration;3) 22-integrin affinity and bond mechanics in binding ICAM-1 provide a gatekeeper mechanism via regulation of outside-in signaling of transendothelial migration. In this competitive renewal we apply our innovative vascular mimetic microfluidic channels combined with real-time immunofluorescence imaging to pursue the following specific aims: 1) Examine the role of calcium release activated calcium flux in orchestration of the multistep process of neutrophil recruitment. 2) Determine how E-selectin ligands on neutrophils serve as mechano-transducers that trigger and amplify chemokine signaling of integrin activation on inflamed endothelium 3) define the molecular and mechanical mechanisms underlying LFA-1 outside-in signaling of neutrophil shape polarization. Our strategy entails the use of freshly isolated human neutrophils and murine models of inflammation with the overarching goal of identifying regulatory pathways and molecular targets for prognosis and treatment of inflammatory diseases.

Public Health Relevance

White blood cell emigration into inflamed tissue is likened to a double edged sword, it is critical to innate immune defense against bacterial infection, but if unchecked contributes to autoimmune disease and tissue destruction. We develop technologies to measure how neutrophils, the most common white cell, adhere to blood vessels and migrate to sites of inflammation in order to design more effective anti-inflammatory therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047294-15
Application #
8497567
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Minnicozzi, Michael
Project Start
1999-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$367,105
Indirect Cost
$120,895
Name
University of California Davis
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Block, Helena; Stadtmann, Anika; Riad, Daniel et al. (2016) Gnb isoforms control a signaling pathway comprising Rac1, Plcβ2, and Plcβ3 leading to LFA-1 activation and neutrophil arrest in vivo. Blood 127:314-24
Waffarn, Elizabeth E; Hastey, Christine J; Dixit, Neha et al. (2015) Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. Nat Commun 6:8991
Foster, Greg A; Xu, Lu; Chidambaram, Alagu A et al. (2015) CD11c/CD18 Signals Very Late Antigen-4 Activation To Initiate Foamy Monocyte Recruitment during the Onset of Hypercholesterolemia. J Immunol 195:5380-92
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Krishnamurthy, Venkata R; Sardar, Mohammed Y R; Ying, Yu et al. (2015) Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo. Nat Commun 6:6387
Uchiyama, Satoshi; Döhrmann, Simon; Timmer, Anjuli M et al. (2015) Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus. Front Immunol 6:581
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Kim, Min-Ho; Gorouhi, Farzam; Ramirez, Sandra et al. (2014) Catecholamine stress alters neutrophil trafficking and impairs wound healing by β2-adrenergic receptor-mediated upregulation of IL-6. J Invest Dermatol 134:809-17
Altman, Stuart M; Dixit, Neha; Simon, Scott I (2014) Detection of bidirectional signaling during integrin activation and neutrophil adhesion. Methods Mol Biol 1124:235-48
Kusunose, Jiro; Zhang, Hua; Gagnon, M Karen J et al. (2013) Microfluidic system for facilitated quantification of nanoparticle accumulation to cells under laminar flow. Ann Biomed Eng 41:89-99

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