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

X Huang, F Venet, YL Wang… - Proceedings of the …, 2009 - National Acad Sciences
X Huang, F Venet, YL Wang, A Lepape, Z Yuan, Y Chen, R Swan, H Kherouf, G Monneret
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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.
National Acad Sciences