title: Fibrinogen regulates the cytotoxicity of mycobacterial trehalose dimycolate but is not required for cell recruitment, cytokine response, or control of mycobacterial infection.
abstract: During inflammatory responses and wound healing, the conversion of soluble fibrinogen to fibrin, an insoluble extracellular matrix, long has been assumed to create a scaffold for the migration of leukocytes and fibroblasts. Previous studies concluded that fibrinogen is a necessary cofactor for mycobacterial trehalose 6,6'-dimycolate-induced responses, because trehalose dimycolate-coated beads, to which fibrinogen was adsorbed, were more inflammatory than those to which other plasma proteins were adsorbed. Herein, we investigate roles for fibrin(ogen) in an in vivo model of mycobacterial granuloma formation and in infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. In wild-type mice, the subcutaneous injection of trehalose dimycolate-coated polystyrene microspheres, suspended within Matrigel, elicited a pyogranulomatous response during the course of 12 days. In fibrinogen-deficient mice, neutrophils were recruited but a more suppurative lesion developed, with the marked degradation and disintegration of the matrix. Compared to that in wild-type mice, the early formation of granulation tissue in fibrinogen-deficient mice was edematous, hypocellular, and disorganized. These deficiencies were complemented by the addition of exogenous fibrinogen. The absence of fibrinogen had no effect on cell recruitment or cytokine production in response to trehalose dimycolate, nor was there a difference in lung histopathology or overall bacterial burden in mice infected with Mycobacterium tuberculosis. In this model, fibrin(ogen) was not required for cell recruitment, cytokine response, or response to infection, but it promoted granulation tissue formation and suppressed leukocyte necrosis.
authors.affiliation: Department of Pathology, College of Veterinary Medicine, 501 D. W. Brooks Dr., University of Georgia, Athens, GA 30602-7388, USA. kaoris@uga.edu
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Geisel
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Bryce T
authors.initials: BT
authors.lastname: Wyatt
authors.forename: Llewelyn B
authors.initials: LB
authors.lastname: Sellers
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Rhoades
mesh_terms: D000818:Animals; D003311:Cord Factors / Q000276:immunology / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000276:immunology*; D006099:Granuloma / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000276:immunology*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012867:Skin / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D003311:Cord Factors; D016207:Cytokines; D005340:Fibrinogen