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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.cosignaling molecule ͉ inflammation ͉ innate immunity ͉ PD-1 ͉ sepsis

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

“…Concomitantly, the bacterial colonization was significantly lower in the peritoneal cavity and blood of LysM-Keap1 2/2 mice compared with LysMNrf2 2/2 or Keap1 f/f . Peritoneal macrophages from septic mice are associated with impaired bacterial phagocytic ability (24). We found greater bacterial phagocytic ability of peritoneal macrophages isolated from LysM-Keap1 2/2 compared with LysMNrf2 2/2 or Keap1 f/f after CLP.…”

“…No significant difference in the leukocyte cell number between LysM-Keap1 2/2 and floxed control groups was noted ( Figure 4C). Macrophages from septic mice show impaired bacterial phagocytosis and are well correlated with bacterial burden and mortality (24). To determine whether Nrf2 signaling effects bacterial phagocytosis, we analyzed ex vivo bacterial phagocytic activity in peritoneal macrophages isolated from LysM-Keap1…”

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

“…Because PD-1 −/− mice developed a MOG -specific Th17 response to EAE immunizations with low doses of HKMTB, PD-1 −/− mice may have intrinsic properties to exhibit augmented response to HKMTB, which results in enhanced induction of Th17. As PD-1 is expressed on innate cells (31,32) as well as T and B cells, PD-1 may regulate innate response that influences T-cell activation. To address this point, we established a system in which we can separately evaluate the function of PD-1 in the innate and the acquired immune responses.…”

Peroxisome Proliferator-activated Receptor γ Co-activator 1-α as a Critical Co-activator of the Murine Hepatic Oxidative Stress Response and Mitochondrial Biogenesis in Staphylococcus aureus Sepsis

“…Activation of mPD-1 was initially reported in apoptotic lymphoid cell lines in mice (45), and the protein is well known to repress the immune response by inhibiting T cells and decreasing cytokine synthesis (46). More recently, the protein was implicated in the immune response to sepsis because the knock-out mice exhibit decreased lymphocyte apoptosis in sepsis (47) and show improved regional and systemic bacterial clearance after cecal ligation and puncture (48). In human patients, differences in mPD-1 levels in sepsis survivors versus nonsurvivors correlate with rates of secondary nosocomial infections (49).…”