title: PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis.
abstract: 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.
authors.affiliation: Division of Surgical Research, Department of Surgery, Brown University School of Medicine/Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Fabienne
authors.initials: F
authors.lastname: Venet
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Wang
authors.forename: Alain
authors.initials: A
authors.lastname: Lepape
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Yuan
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.forename: Ryan
authors.initials: R
authors.lastname: Swan
authors.forename: Hakim
authors.initials: H
authors.lastname: Kherouf
authors.forename: Guillaume
authors.initials: G
authors.lastname: Monneret
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala