title: Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin.
abstract: Lung injury can release intracellular actin into the alveolar milieu and is also associated with increased susceptibility to secondary infections. We investigated the effect of free (extracellular) actin on lung macrophage host defense functions. Western blot analysis demonstrated free actin release into the lung lavage fluids of mouse models of ozone injury, influenza infection, and secondary pneumococcal pneumonia and in samples from patients following burn and inhalation injury. Using levels comparable with those observed in lung injury, we found that free actin markedly inhibited murine lung macrophage binding and uptake in vitro ofS. pneumoniae,S. aureus, andE. coli, (e.g.,S. pneumoniae, mean %inhibition, actin vs. vehicle: 85 ± 0.3 (SD);n= 22,P< .001). Similar effects were observed on the ability of primary human macrophages to bind and ingest fluorescentSaureus(~75% inhibition). Plasma gelsolin (pGSN), a protein that functions to bind and cleave actin, restored bacterial binding and uptake by both murine and human macrophages. Scavenger receptor inhibitors reduced binding of fluorescent actin by murine macrophages [fluorescence index (×10-3) after incubation with vehicle, actin, or actin + polyinosinic acid, respectively: 0.8 ± 0.7, 101.7 ± 50.7, or 52.7 ± 16.9;n= 5-6,P< 0.05]. In addition, actin binding was reduced in a MARCO/SR-AI/II-deficient cell line and by normal AMs obtained from MARCO-/-mice. After release from injured cells during lung injury, free actin likely contributes to impaired host defense by blocking scavenger receptor binding of bacteria. This mechanism for increased risk of secondary infections after lung injury or inflammation may represent another target for therapeutic intervention with pGSN.
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ordija
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Terry Ting-Yu
authors.initials: TT
authors.lastname: Chiou
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Deloid
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Melina
authors.initials: M
authors.lastname: de Oliveira Valdo
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Alice
authors.initials: A
authors.lastname: Bedugnis
authors.affiliation: Department of Pediatrics, Pulmonology Division, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Noah
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Samuel
authors.initials: S
authors.lastname: Jones
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Henry
authors.initials: H
authors.lastname: Koziel
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; lkobzik@hsph.harvard.edu.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001419:Bacteria / Q000276:immunology; D005260:Female; D018260:Gelsolin / Q000097:blood*; D006801:Humans; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000378:metabolism*
chemical_list: D000199:Actins; D018260:Gelsolin; C092228:Marco protein, mouse; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger
keywords: actin; alveolar macrophages; plasma gelsolin; scavenger receptors