title: Sepsis-induced potentiation of peritoneal macrophage migration is mitigated by programmed cell death receptor-1 gene deficiency.
abstract: The effect of programmed cell death receptor-1 (PD-1) on phagocyte function has not been extensively described. Here we report that experimental mouse sepsis, cecal ligation and puncture (CLP), induced a marked increase in peritoneal macrophage random migration, motility and cell spread, but these changes were lost in the absence of PD-1. Alternatively, phagocytic activity was inversely affected. In vitro cell culture imaging studies, with the macrophage cell line J774, documented that blocking PD-1 with antibody led to aggregation of the cytoskeletal proteins α-actinin and F-actin. Further experiments looking at ex vivo peritoneal macrophages from mice illustrated that a similar pattern of α-actinin and F-actin was evident on cells from wild-type CLP mice but not PD-1-/- CLP mouse cells. We also observed that fMLP-induced migration by J774 cells was markedly attenuated using PD-1 blocking antibodies, a nonselective phosphatase inhibitor and a selective Ras-related protein 1 inhibitor. Finally, peritoneal macrophages derived from CLP as opposed to Sham mice demonstrated aspects of both cell surface co-localization with CD11b and internalization of PD-1 within vacuoles independent of CD11b staining. Together, we believe the data support a role for PD-1 in mediating aspects of innate macrophage immune dysfunction during sepsis, heretofore unappreciated.
authors.affiliation: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, R.I., USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Gwendolyn F
authors.initials: GF
authors.lastname: Elphick
authors.forename: Ye Sul
authors.initials: YS
authors.lastname: Kim
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Carreira-Rosario
authors.forename: Sadella C
authors.initials: SC
authors.lastname: Santos
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shubin
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Reichner
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
mesh_terms: D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D002432:Cecum / Q000601:surgery; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport; D018805:Sepsis / Q000276:immunology*
chemical_list: D000199:Actins; D019138:Antibodies, Blocking; D039481:CD11b Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000185:Actinin