Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis.
Recent studies suggest that coinhibitory receptors appear to be important in contributing sepsis-induced immunosuppression. Our laboratory reported that mice deficient in programmed cell death receptor (PD)-1 have increased bacterial clearance and improved survival in experimental sepsis induced by cecal ligation and puncture (CLP). In response to infection, the liver clears the blood of bacteria and produces cytokines. Kupffer cells, the resident macrophages in the liver, are strategically situated to perform the above functions. However, it is not known if PD-1 expression on Kupffer cells is altered by septic stimuli, let alone if PD-1 ligation contributes to the altered microbial handling seen. Here we report that PD-1 is significantly upregulated on Kupffer cells during sepsis. PD-1-deficient septic mouse Kupffer cells displayed markedly enhanced phagocytosis and restoration of the expression of major histocompatibility complex II and CD86, but reduced CD80 expression compared with septic wild-type (WT) mouse Kupffer cells. In response to ex vivo LPS stimulation, the cytokine productive capacity of Kupffer cells derived from PD-1-/- CLP mice exhibited a marked, albeit partial, restoration of the release of IL-6, IL-12, IL-1β, monocyte chemoattractant protein-1, and IL-10 compared with septic WT mouse Kupffer cells. In addition, PD-1 gene deficiency decreased LPS-induced apoptosis of septic Kupffer cells, as indicated by decreased levels of cleaved caspase-3 and reduced terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. Exploring the signal pathways involved, we found that, after ex vivo LPS stimulation, septic PD-1-/- mouse Kupffer cells exhibited an increased Akt phosphorylation and a reduced p38 phosphorylation compared with septic WT mouse Kupffer cells. Together, these results indicate that PD-1 appears to play an important role in regulating the development of Kupffer cell dysfunction seen in sepsis.
Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai, PR China; and.
Fei
F
Wang
Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, Rhode Island.
Xin
X
Huang
Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, Rhode Island.
Chun-Shiang
CS
Chung
Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, Rhode Island.
Yaping
Y
Chen
Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, Rhode Island.
Noelle A
NA
Hutchins
Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, Rhode Island aayala@lifespan.org.
Alfred
A
Ayala
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D060085:Coinfection / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D007728:Kupffer Cells / Q000378:metabolism* / Q000382:microbiology; D008099:Liver / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D010641:Phenotype; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
Akt; MAPK p38; PU.1; coinhibitory molecules; cytokines; liver macrophages; phagocytosis; septic inflammation