Abstract
We have shown that invariant natural killer T (iNKT) cells mediate sepsis-induced end-organ changes and immune responses, including macrophage bacterial phagocytosis, a finding regulated by the check point protein program cell death receptor-1 (PD-1). Furthermore, PD-1 mediates mortality in both adult and neonatal murine sepsis as well as in surgical patients. Given our previous findings, we hypothesize that iNKT cells will also modulate neonatal sepsis survival, and that this effect is regulated in part through PD-1. We utilized a polymicrobial intra-peritoneal cecal slurry (CS) sepsis model in wild type (WT), iNKT−/− or PD-1−/− 5–7 day old neonatal pups. Typically, tissues were harvested at 24 h for various bioassays/histology and, in some cases, survival was assessed for up to 7 days. Interestingly, similar to what we recently reported for PD-1−/− mice following CS, iNKT−/−-deficient animals exhibit a markedly improved survival vs. WT. Histologically, minor alterations in liver architectural, which were noted in WT pups, were attenuated in both iNKT−/− and PD-1−/− pups. Following CS, PECAM-1 expression was unchanged in the WT pups but increased in both iNKT−/− and PD-1−/− pups. In WT, following CS the emergence of a Ly6Clow subpopulation was noted among the influxed peritoneal macrophage population. Conversely, within iNKT−/− pups, there were fewer peritoneal macrophages and a greater percentage of Ly6Chigh macrophages. We show not only a key role for iNKT cells in affecting end-organ damage as well as alterations in phagocytes phenotypes in neonatal sepsis but that this iNKT cell mediated effect is driven by the central checkpoint protein PD-1.
Highlights
Sepsis in neonates remains a devastating illness
We demonstrated a role for the check point protein program cell death receptor-1 (PD-1) in modulating the mortality seen with isolated peritoneal polymicrobial sepsis [4]
Given our finding that invariant natural killer T (iNKT) cells play a role in modulating mortality from sepsis in adult mice [11, 13], we first undertook a survival analysis to assess for a potential role for iNKT cells in neonatal sepsis
Summary
Despite significant advances in medical and surgical ICU care, both sepsis-related mortality and long-term morbidity from residual multiorgan dysfunction remain dismally high [1, 2]. Intra-abdominal sepsis, from a variety of causes, remains a leading etiology of neonatal sepsis. PD-1 and iNKT-Cells Neonatal Sepsis disease such as necrotizing enterocolitis by including a variety of components to the models [3]. There is a paucity of data pertaining to the isolated effect of the abdominal bacterial burden without a significant tissue damage component. We demonstrated a role for the check point protein program cell death receptor-1 (PD-1) in modulating the mortality seen with isolated peritoneal polymicrobial sepsis [4]. PD-1 is a check point protein involved in both co-stimulatory and co-inhibitory regulation of a variety of acute and chronic immune responses [4,5,6,7]
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