title: Impaired function of Fanconi anemia type C-deficient macrophages.
abstract: FA is a genetic disorder characterized by BM failure, developmental defects, and cancer predisposition. Previous studies suggest that FA patients exhibit alterations in immunologic function. However, it is unclear whether the defects are immune cell-autonomous or secondary to leukopenia from evolving BM failure. Given the central role that macrophages have in the innate immune response, inflammation resolution, and antigen presentation for acquired immunity, we examined whether macrophages from Fancc-/- mice exhibit impaired function. Peritoneal inflammation induced by LPS or sodium periodate resulted in reduced monocyte/macrophage recruitment in Fancc-/- mice compared with WT controls. Fancc-/- mice also had decreased inflammatory monocytes mobilized into the peripheral blood after LPS treatment compared with controls. Furthermore, Fancc-/- peritoneal macrophages displayed cell-autonomous defects in function, including impaired adhesion to FN or endothelial cells, reduced chemoattractant-mediated migration, and decreased phagocytosis. Moreover, dysregulated F-actin rearrangement was detected in Fancc-/- macrophages after adhesion to FN, which was consistent with an observed reduction in RhoA-GTP levels. Importantly, these data suggest that impaired cytoskeletal rearrangements in Fancc-/- macrophages may be the common mechanism responsible for cell-autonomous defects detected in vitro, as well as altered monocyte/macrophage trafficking in vivo.
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Ying
authors: Y
authors: Liu
authors: Kimberly
authors: K
authors: Ballman
authors: Deqiang
authors: D
authors: Li
authors: Shehnaz
authors: S
authors: Khan
authors: Ethel
authors: E
authors: Derr-Yellin
authors: Weinian
authors: W
authors: Shou
authors: Laura S
authors: LS
authors: Haneline
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000737:chemistry / Q000648:ultrastructure; D042783:Endothelial Cells / Q000166:cytology; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010587:Phagocytosis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000502:physiology; D020742:rhoA GTP-Binding Protein
chemical_list: D000199:Actins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013481:Superoxides; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein