title: WFDC1 is a key modulator of inflammatory and wound repair responses.
abstract: WFDC1/ps20 is a whey acidic protein four-disulfide core member that exhibits diverse growth and immune-associated functions in vitro. In vivo functions are unknown, although WFDC1 is lower in reactive stroma. A Wfdc1-null mouse was generated to assess core functions. Wfdc1-null mice exhibited normal developmental and adult phenotypes. However, homeostasis challenges affected inflammatory and repair processes. Wfdc1-null mice infected with influenza A exhibited 2.75-log-fold lower viral titer relative to control mice. Wfdc1-null infected lungs exhibited elevated macrophages and deposition of osteopontin, a potent macrophage chemokine. In wounding studies, Wfdc1-null mice exhibited an elevated rate of skin closure, and this too was associated with elevated deposition of osteopontin and macrophage recruitment. Wfdc1-null fibroblasts exhibited impaired spheroid formation, elevated adhesion to fibronectin, and an increased rate of wound closure in vitro. This was reversed by neutralizing antibody to osteopontin. Osteopontin mRNA and cleaved protein was up-regulated in Wfdc1-null cells treated with lipopolysaccharide or polyinosinic-polycytidylic acid coordinate with constitutively active matrix metallopeptidase-9 (MMP-9), a protease that cleaves osteopontin. These data suggest that WFDC1/ps20 modulates core host response mechanisms, in part, via regulation of osteopontin and MMP-9 activity. Release from WFDC1 regulation is likely a key component of inflammatory and repair response mechanisms, and involves the processing of elevated osteopontin by activated MMP-9, and subsequent macrophage recruitment.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ressler
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Truong D
authors.initials: TD
authors.lastname: Dang
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
authors.forename: Dennis Y
authors.initials: DY
authors.lastname: Tse
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gilbert
authors.affiliation: Department of Infectious Diseases, King's College London, London, United Kingdom.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Vyakarnam
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Isaiah G
authors.initials: IG
authors.lastname: Schauer
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Barron
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Electronic address: drowley@bcm.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Rowley
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*
chemical_list: D005353:Fibronectins; D011506:Proteins; C484311:Wfdc1 protein, mouse; D053495:Osteopontin; D020780:Matrix Metalloproteinase 9