PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 15; pp. 6303 - 6308
• Main Authors: Huang, Xin, Venet, Fabienne, Wang, Yvonne L, Lepape, Alain, Yuan, Zhenglong, Chen, Yaping, Swan, Ryan, Kherouf, Hakim, Monneret, Guillaume, Chung, Chun-Shiang, Ayala, Alfred
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14-04-2009; National Acad Sciences
• Subjects: Animals; Antigens, CD - metabolism; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Antimicrobial agents; Apoptosis Regulatory Proteins - metabolism; Bacteria; Biological Sciences; Biomarkers; Bisphosphonates; Blood; Clodronic acid; Coculture Techniques; Cytokines; Cytokines - immunology; Data processing; Gene expression; Gene Expression Regulation; Humans; Immune response; Immunity, Innate - immunology; Inflammation; Lethality; Liposomes; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Knockout; Monocytes; Pathology; PD-1 protein; Peritoneal macrophages; Peritoneum; Programmed Cell Death 1 Receptor; Rodents; Sepsis; Sepsis - genetics; Sepsis - immunology; Sepsis - metabolism; Sepsis - pathology; Septic shock; Survival Rate; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0809422106

Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1⁻/⁻ mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1⁻/⁻ mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.