Neonatal monocytes express antiapoptotic pattern of Bcl-2 proteins and show diminished apoptosis upon infection with Escherichia coli

Abstract

Background:Neonates show sustained inflammation after a bacterial infection, which is associated with inflammatory diseases like bronchopulmonary dysplasia or periventricular leucomalacia. Physiologically, inflammation is terminated early after the removal of the invading pathogens by phagocytosisinduced cell death (PICD) of immune effector cells. Earlier results showed reduced PICD in neonatal monocytes. The underlying molecular mechanisms are unknown. We hypothesize that the reduced PICD in neonatal monocytes is regulated through the proteins of the B-cell lymphoma 2 (Bcl-2) protein family. Methods: mRNA and protein expression of Bcl-2 family proteins in cord blood and adult peripheral blood monocytes infected with Escherichia coli were analyzed by quantitative real-time PCR and flow cytometry and cytochrome c release by fluorescence microscopy. results: mRNA expression of antiapopototic Bcl-xL was upregulated in cord blood monocytes (CBMO), whereas proapoptotic Bim tended to be higher in peripheral blood monocytes (PBMO). Upon infection, Bax was more strongly expressed in PBMO compared with CBMO. The pro/antiapoptotic balance was skewed toward survival in CBMO and apoptosis in PBMO. Cytochome c release into the cytosol was enhanced in PBMO compared with CBMO. conclusion: Bcl-2 proteins are involved in reduced PICD in neonatal monocytes. These findings are another step toward the understanding of sustained inflammation in neonates.

Neonatal myeloid derived suppressor cells show reduced apoptosis and immunosuppressive activity upon infection with Escherichia coli

“…Inflammation seems to be a key regulatory factor for MDSC survival [24] since apoptosis may be induced by activation of the Fas-FasL pathway. We have lately shown that cord blood monocytes also show reduced apoptosis upon infection because of diminished FasL-secretion and increased expression of anti-apoptotic Bcl-proteins [16,25]. Concordantly, our present results show higher expression of the anti-apoptotic protein Bcl-2 in G-MDSC compared to PMN, and blocking Bcl-2 led to increased apoptosis rates ( Fig.…”

“…Early steps of apoptosis include externalisation of phosphatidylserine and the loss of mitochondrial membrane potential (MMP) leading to cytochrome c release and activation of effector caspases resulting in DNA‐cleavage and apoptotic demise . Infection‐associated production of reactive oxygen species (ROS) and the expression of B‐cell lymphoma 2 (Bcl‐2) family proteins have been shown as involved in regulating infection‐induced apoptosis.…”

Reduced internalization of TNF-ɑ/TNFR1 down-regulates caspase dependent phagocytosis induced cell death (PICD) in neonatal monocytes

“…coli- infected purified monocytes have been described [ 19 ] [ 20 – 22 ]. Dampening inflammation is thought to be essential for the fetal immune system to avoid rejection by the mother and termination of pregnancy [ 23 ]. Therefore reduced secretion of TNF-α could be beneficial for the fetal environment, albeit bearing the risk of reduced capacity to fight of infection and of prolonged activation of immune effector cells by due to missing pro-apoptotic signaling.…”

“…Evidence for phagocytosis-triggered activation of the pro-apoptotic cascade involving caspases -8 and -3, was described for Staphylococcus aureus [ 28 ]. Phagocytosis also regulates the expression of small Bcl-2 like proteins [ 23 ]. For the BCL-2 like protein t-Bid a connecting function to the extrinsic and intrinsic apoptosis cascade could be shown [ 29 ], defining caspase-8 as a hinge in an auto-activating loop accelerating apoptosis.…”

The phenotype and function of preterm infant monocytes: implications for susceptibility to infection

“…Infection can also induce pyroptosis; a rapid form of cell death triggered via the formation of inflammasomes [80]. Several reports indicate that neonatal monocytes exhibit significantly reduced apoptosis following E. coli or GBS infection compared to adults, which has been associated with the up-regulated transcription of antiapoptotic proteins [81][82][83]. No studies have specifically investigated cell death in preterm infant monocytes; however, this would be informative, as decreased apoptosis may help explain the persistent inflammation that has been described during the neonatal period in very preterm infants [84].…”