Biomaterials differentially regulate Src kinases and phosphoinositide 3-kinase-γ in polymorphonuclear leukocyte primary and tertiary granule release.
In the foreign body response, infiltrating PMNs exocytose granule subsets to influence subsequent downstream inflammatory and wound healing events. In previous studies, we found that PMNs cultured on poly(ethylene glycol) (PEG)-containing hydrogels (i.e., PEG and gelatin + PEG hydrogels) had enhanced primary granule release, yet similar tertiary granule release compared with PMNs cultured on polydimethylsiloxane or tissue culture polystyrene. PMN primary granules contain microbicidal proteins and proteases, which can potentially injure bystander cells, degrade the extracellular matrix, and promote inflammation. Here, we sought to understand the mechanism of the enhanced primary granule release from PMNs on PEG hydrogels. We found that primary granule release from PMNs on PEG hydrogels was adhesion mediated and involved Src family kinases and PI3K-γ. The addition of gelatin to PEG hydrogels did not further enhance PMN primary granule release. Using stable-isotope dimethyl labeling-based shotgun proteomics, we identified many serum proteins - including Ig gamma constant chain region proteins and alpha-1-acid glycoprotein 1 - that were absorbed/adsorbed in higher quantities on PEG hydrogels than on TCPS, and may be involved in mediating PMN primary granule release. Ultimately, this mechanistic knowledge can be used to direct inflammation and wound healing following biomaterial implantation to promote a more favorable healing response.
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
Hannah Caitlin
HC
Cohen
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
Dustin C
DC
Frost
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.
Tyler Jacob
TJ
Lieberthal
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA.
Lingjun
L
Li
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: wjkao@wisc.edu.
W John
WJ
Kao
D000327:Adsorption; D000328:Adult; D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D002417:Cattle; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011137:Polystyrenes / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D001672:Biocompatible Materials; D001798:Blood Proteins; D020100:Hydrogels; D011137:Polystyrenes; D044042:Receptors, Formyl Peptide; D011092:Polyethylene Glycols; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9
Acute inflammation; Degranulation; Gelatin; Neutrophil; Poly(ethylene glycol); Protein adsorption