Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo.
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.
Tharp
William G
WG
Infectious Diseases Division and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Yadav
R
R
Irimia
D
D
Upadhyaya
A
A
Samadani
A
A
Hurtado
O
O
Liu
S-Y
SY
Munisamy
S
S
Brainard
D M
DM
Mahon
M J
MJ
Nourshargh
S
S
van Oudenaarden
A
A
Toner
M G
MG
Poznansky
Mark C
MC
D000818:Animals; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D000242:Cyclic AMP / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D016209:Interleukin-8 / Q000276:immunology* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism
D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins