Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo

Journal of Leukocyte Biology

R. Yadav³  O. Hurtado²  M. G. Toner²  D. M. Brainard⁵  S. Munisamy⁵  D. Irimia²  William G. Tharp⁵  M. J. Mahon⁶  S. Nourshargh³  S-Y. Liu¹  A. Upadhyaya⁴  A. Samadani⁴  Mark C. Poznansky⁵  A. van Oudenaarden⁴ 

[1] Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston; and Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston; and Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston; andCardiovascular Medicine Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom; Cardiovascular Medicine Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom; Cardiovascular Medicine Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom;Department of Physics, Massachusetts Institutes of Technology, Boston; Department of Physics, Massachusetts Institutes of Technology, Boston; Department of Physics, Massachusetts Institutes of Technology, Boston;Infectious Diseases Division and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston; Infectious Diseases Division and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston; Infectious Diseases Division and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston;;Endocrine Unit, Massachusetts General Hospital, Boston Endocrine Unit, Massachusetts General Hospital, Boston Endocrine Unit, Massachusetts General Hospital, Boston

关键词: chemotaxis;    microfluidics;    gradient;   

DOI  :  10.1189/jlb.0905516

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

We report for the first time that primary human neutrophils can undergo persistent, directionally biased movement away from a chemokine in vitro and in vivo, termed chemorepulsion or fugetaxis. Robust neutrophil chemorepulsion in microfluidic gradients of interleukin-8 (IL-8; CXC chemokine ligand 8) was dependent on the absolute concentration of chemokine, CXC chemokine receptor 2 (CXCR2), and was associated with polarization of cytoskeletal elements and signaling molecules involved in chemotaxis and leading edge formation. Like chemoattraction, chemorepulsion was pertussis toxin-sensitive and dependent on phosphoinositide-3 kinase, RhoGTPases, and associated proteins. Perturbation of neutrophil intracytoplasmic cyclic adenosine monophosphate concentrations and the activity of protein kinase C isoforms modulated directional bias and persistence of motility and could convert a chemorepellent to a chemoattractant response. Neutrophil chemorepulsion to an IL-8 ortholog was also demonstrated and quantified in a rat model of inflammation. The finding that neutrophils undergo chemorepulsion in response to continuous chemokine gradients expands the paradigm by which neutrophil migration is understood and may reveal a novel approach to our understanding of the homeostatic regulation of inflammation.

【 授权许可】

Unknown