title: Shear-induced resistance to neutrophil activation via the formyl peptide receptor.
abstract: The application of fluid shear stress on leukocytes is critical for physiological functions including initial adhesion to the endothelium, the formation of pseudopods, and migration into tissues. The formyl peptide receptor (FPR) on neutrophils, which binds to formyl-methionyl-leucyl-phenylalanine (fMLP) and plays a role in neutrophil chemotaxis, has been implicated as a fluid shear stress sensor that controls pseudopod formation. The role of shear forces on earlier indicators of neutrophil activation, such as L-selectin shedding and α(M)β(2) integrin activation, remains unclear. Here, human neutrophils exposed to uniform shear stress (0.1-4.0 dyn/cm(2)) in a cone-and-plate viscometer for 1-120 min showed a significant reduction in both α(M)β(2) integrin activation and L-selectin shedding after stimulation with 0.5 nM of fMLP. Neutrophil resistance to activation was directly linked to fluid shear stress, as the response increased in a shear stress force- and time-dependent manner. Significant shear-induced loss of FPR surface expression on neutrophils was observed, and high-resolution confocal microscopy revealed FPR internalized within neutrophils. These results suggest that physiological shear forces alter neutrophil activation via FPR by reducing L-selectin shedding and α(M)β(2) integrin activation in the presence of soluble ligand.
authors: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors: Michael J
authors: MJ
authors: Mitchell
authors: Michael R
authors: MR
authors: King
mesh_terms: D001696:Biomechanical Phenomena; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D033081:Shear Strength / Q000187:drug effects; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D011480:Protease Inhibitors; D044042:Receptors, Formyl Peptide; D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine