Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency

• Published in: Journal of innate immunity Vol. 6; no. 3; pp. 325 - 338
• Main Authors: Ayala, Alfred, Elphick, Gwendolyn F., Kim, Ye Sul, Huang, Xin, Carreira-Rosario, Arnaldo, Santos, Sadella C., Shubin, Nicholas J., Chen, Yaping, Reichner, Jonathan, Chung, Chun-Shiang
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2014
• Subjects: Actinin - metabolism; Actins - metabolism; Animals; Antibodies, Blocking - pharmacology; CD11b Antigen - metabolism; Cecum - surgery; Cell death; Cell Line; Cell Movement - drug effects; Cell Movement - genetics; Disease Models, Animal; Humans; Immunity, Innate; Macrophage Activation; Macrophages, Peritoneal - immunology; Male; Mice, Inbred C57BL; Mice, Knockout; Phagocytosis - drug effects; Phagocytosis - genetics; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Protein Transport; Research Article; Sepsis - immunology; Signal transduction; Sepsis; Macrophages; Migration; Phagocytosis; Co-inhibitory molecule
• ISSN: 1662-811X; 1662-8128
• DOI: 10.1159/000355888

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.