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.

A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis

“…Additionally, random migratory capacity (measured both in rate and direction) and cell spreading (following surface adherence) increased markedly after sepsis among WT mice. Importantly, these phenomena were equivalent to findings among sham control samples in the setting of PD-1 gene deficiency (96). These latter changes in migratory capacity, cell spreading and motility, appear to be partly due to PD-1-mediated changes in cytoskeletal alpha-actinin and F-actin aggregation capabilities.…”

“…Importantly, these phenomena were equivalent to findings among sham control samples in the setting of PD-1 gene deficiency. 96 to clearance of the invading pathogen. 97 However, it is also thought that the recruitment of activated PMNs may be harmful when these functions are directed at otherwise normal host tissue (bystander injury).…”

The new normal: immunomodulatory agents against sepsis immune suppression

“…Although more studies are being performed to investigate the roles of cell surface co-inhibitory molecules in critically ill patient and animal models, few investigators have considered whether these molecules function alone or cooperatively in vivo with other cell surface molecules and/or if there is functional redundancy between each molecule [88]. Most of what we know about these molecules as suggested therapies, particularly CTLA-4, and PD-1, has come from clinical trials in cancer and studies of their roles in viral infections, suggesting that these two molecules block regulatory T cell effector functions, encourage robust CD8 + T cell responses against tumors and paralyze anti-viral T cell motility [89, 90].…”

“…For example, it has also been proposed that PD-L1 expression in the liver plays a role in attenuating acute liver injury in sepsis animal models [91, 92]. Based on experimental animal and human data with PD-1, we propose that an ideal anti-PD-1 therapy in sepsis would enhance monocyte/macrophage phagocytic function as well as T cell function, because the expression of PD-1 on macrophages/monocytes potentially also leads to sepsis-induced immune dysfunction (Figure 4) [36, 88]. …”

Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis

“…Recent studies suggest that coinhibitory receptors, including PD-1, cytotoxic T-lymphocyte-associated protein-4, and Band T-lymphocyte attenuator, appear to be important in contributing to sepsis-induced immunosuppression (33,38). Our laboratory reported that mice deficient in PD-1 have increased bacterial clearance and improved survival in experimental sepsis (4,18,30). In response to infection, the liver clears the blood of bacteria and produces cytokines.…”