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Phosphoinositide‐3‐kinase regulation of neutrophil mechanosensing is context dependent
Author(s) -
O'Brien Xian,
Oakley Katie E,
Loosley Alex J,
Tang Jay X,
Reichner Jonathan S
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.650.1
Subject(s) - chemotaxis , fibronectin , integrin , microbiology and biotechnology , chemistry , pi3k/akt/mtor pathway , chemokine , regulator , immunology , receptor , signal transduction , biology , extracellular matrix , biochemistry , gene
To localize to an injury or infection, neutrophils interpret biochemical and physical cues. Previously, we have shown that neutrophil chemotaxis on fibronectin (Fn) is also regulated by mechanical stiffness through a phosphoinositide‐3‐kinase (PI3K) dependent mechanism. To determine whether substrate stiffness is a universal regulator of function, we quantified human neutrophil migration dynamics on fibrinogen (Fgn), collagen (Col), and Fn, integrin ligands encountered during an inflammatory response. As an inflammatory matrix includes multiple ligands, we also analyzed neutrophils on mixtures of Fn and Fgn. Analysis of mean square displacement, rate of migration, chemotactic index and cell polarity identified ligand‐specific mechanosensitivity influenced by both beta 1 and 2 integrins. Stiffness‐dependent changes in migration and cell polarity varied by ligand, with mechanospecific changes in migration observed on Fn, Col, and mixtures of Fn and Fgn, but not Fgn alone. Inhibitor studies show the role of PI3K in regulating neutrophil polarization and mechanotactic migration dynamics increases in complexity with the model system. Our data show that PI3K can act to either facilitate or inhibit neutrophil chemotaxis toward fMLP with protein substrate and stiffness determining this contextual regulation. Supported by grants from the NIH, the NSF's MRSEC at Brown, and RI Hospital.