Reduced internalization of TNF-[alpha]/TNFR1 down-regulates caspase dependent phagocytosis induced cell death

• Published in: PloS one Vol. 12; no. 8; p. e0182415
• Main Authors: Dreschers, Stephan, Gille, Christian, Haas, Martin, Seubert, Florence, Platen, Christopher, Orlikowsky, Thorsten W
• Format: Journal Article
• Language: English
• Published: Public Library of Science 09.08.2017
• Subjects: Apoptosis; Health aspects; Infection; Inflammation; Monocytes; Phagocytosis; Risk factors; Tumor necrosis factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182415

Phagocytosis-induced cell death (PICD) is diminished in cord blood monocytes (CBMO) as compared to cells from adults (PBMO) due to differences in the CD95-pathway. This may support a prolonged pro-inflammatory response with sequels of sustained inflammation as seen in neonatal sepsis. Here we hypothesized that TNF-[alpha] mediated induction of apoptosis is impaired in CBMO due to differences in the TNFR1-dependent internalization. Monocytes were infected with Escherichia coli-GFP (E. coli-GFP). Monocyte phenotype, phagocytic activity, induction of apoptosis, and TNF-[alpha]/TNF-receptor (TNFR) -expression were analysed. In the course of infection TNF-[alpha]-secretion of CBMO was reduced to 40% as compared to PBMO (p<0.05). Neutralization of TNF-[alpha] by an [alpha]TNF-[alpha] antibody reduced apoptotic PICD in PBMO four-fold (p < 0.05 vs. infection with E. coli). PICD in CBMO was reduced 5-fold compared to PBMO and showed less responsiveness to [alpha]TNF-[alpha] antibody. CBMO expressed less pro-apoptotic TNFR1, which, after administration of TNF-[alpha] or infection with E. coli was internalized to a lesser extent. With similar phagocytic capacity, reduced TNFR1 internalization in CBMO was accompanied by lower activation of caspase-8 (p < 0.05 vs. PBMO). Stronger caspase-8 activation in PBMO caused more activation of effector caspase-3 and apoptosis (all p < 0.05 vs. PBMO). Our results demonstrate that TNFR1 internalization is critical in mediating PICD in monocytes after infection with E.coli and is reduced in CBMO.