Analysis of PD-1 expression in the monocyte subsets from non-septic and septic preterm neonates

Abstract

Programmed death-1 (PD-1) receptor system represents a part of recently reported immunoregulatory pathway. PD-1 is an immune checkpoint molecule, which plays an important role in downregulating the immune system proinflammatory activity. Until recently, PD-1 expression was not established on immune cells of the preterm infants. The study objectives were to confirm expression of the PD-1 receptors on the monocytes isolated from very low birth weight newborns (VLBW), and to analyze their expression during the first week of life and late-onset sepsis. Peripheral blood mononuclear cells were isolated from 76 VLBW patients without early-onset sepsis on their 5th day of life (DOL). PD-1 expression was determined on the monocyte subsets (classical, intermediate, non-classical) by flow cytometry. In case of late-onset sepsis (LOS), the same analysis was performed. Our results demonstrated that on the 5th DOL, PD-1 receptors were present in all the monocyte subsets. Children, whose mothers had received antenatal steroids, presented higher absolute numbers of non-classical monocytes with PD-1 expression. Infants born extremely preterm who later developed LOS, initially showed a lower percentage of PD-1 receptor-positive intermediate monocytes in comparison to neonates born very preterm. During LOS, we observed a rise in the percentage of classical monocytes with PD-1 expression. In case of septic shock or fatal outcome, there was a higher percentage and absolute count of intermediate monocytes with PD-1 expression in comparison to children without these complications. In conclusion, monocytes from VLBW children express PD-1 receptors. Antenatal steroid administration seems to induce PD-1 receptor expression in the non-classical monocytes. PD-1 might play a role in immunosuppressive phase of sepsis in the prematurely born children with septic shock and fatal outcome.

Sepsis-Induced Immunosuppression in Neonates

“…Despite the interest in exploring PD-1 blockade for reversing immunosuppression in septic adults, there is a paucity of data pertaining to PD-1 and PD-L1 expression or T cell exhaustion in neonates, and importantly neonates with sepsis. PD-1 expression was increased in 34 VLBW (<1,500 g and GA range ≤ 32 weeks) with confirmed LOS, and expression was significantly increased in 5 preterm infants with septic shock (identified using the international paediatric consensus criteria) and/or mortality ( n = 6) compared to surviving preterm infants without shock ( 81 ). The role of GA on PD-1 expression during neonatal sepsis has not been explored.…”

“…From the limited data available, it appears that fatal neonatal sepsis may be associated with alterations in immune function that are in agreement with SII findings in adults ( 3 , 4 , 6 ). The dysregulated immune responses observed in various neonatal studies include imbalanced secretion of pro- and anti-inflammatory mediators ( 53 – 55 ), diminished HLA-DR monocyte surface expression ( 64 ), expansion of immature neutrophils ( 70 , 71 ), increased expression of PD-1/PD-L1 ( 81 ), and depletion of leukocytes ( 71 , 86 , 87 ). Published neonatal studies are limited by: (i) small sample size of neonates, (ii) incomplete reporting of time from sepsis onset to death, and (iii) the lack of consistent neonatal sepsis definition and objective measures for the degree of severity.…”

MicroRNA‑494‑3p protects rat cardiomyocytes against septic shock via PTEN

“…Large-scale microorganism invasion will cause a stress reaction in tissues and organs. Moderate stress responses may enhance the defensive capacity of the body and control the spread of infection (3); however, prolonged exposure to pathogens can aggravate tissue/organ damage, particularly following a stress reaction (4,5). During septic shock, damaged tissues and organs stimulate the release of large amounts of inflammatory mediators, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, from inflammatory cells, which aggravates the inflammatory response (6).…”

Regulation of Monocyte-Macrophage Responses in Cirrhosis—Role of Innate Immune Programming and Checkpoint Receptors

“…These PD-1 + monocytes secrete suppressive IL-10 upon PD-1 engagement (Figure 2), and either PD-1 or IL-10 receptor blockade in these patients can reverse adaptive HIV-specific T-cell exhaustion(44) (Figure 2). Expression of PD-1 and PD-L1 on monocytes has also been associated with increased mortality in septic patients (45, 46), while expression of TIM-3 on monocytes has been linked to a more aggressive tumor phenotype in gastric cancer patients (47), a reduced pathogen clearance in malaria (48), preferential production of IL-10 and suppression of IFNγ T-cell responses in osteosarcoma patients (49). Furthermore, it has been proposed that expression of TIM-3 on monocytes may be able to shift the balance from IL-12 to IL-23 production and consequently favor type-17 rather than type-1 T-cell responses, driving IL-17-mediated inflammation at the expense of anti-pathogen IFNγ-mediated responses (50, 51) (Figure 2).…”