Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats

Abstract

Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy metabolism. In particular, IFN-γ as well as IL-10-activated CBMΦ completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis. MTOR inhibition by rapamycin equalizes cytokine production in CBMΦ and PBMΦ. Finally, incubation of PBMΦ with cord blood serum or S100A8/A9, which is highly expressed in neonates, suppresses mTOR activation, prevents glycolysis and the expression of an PBMΦ phenotype. Thus, a metabolic alteration is apparent in CBMΦ, which might be dependent on S100A8/A9 expression.

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…In contrast to the murine gut epithelium, postnatal reprogramming of human monocytes was mediated by high perinatal serum concentrations of the endogenous TLR4 ligand S100A8/9 (calprotectin) . The S100A8/9 effect was also observed in cord blood macrophages mediated through inhibition of the mechanistic target of rapamycin pathway and associated with reduced glycolysis . Consistently, dynamic transcriptomic and metabolic changes have been described in human peripheral blood cells during the first week after birth.…”

“…52 The S100A8/9 effect was also observed in cord blood macrophages mediated through inhibition of the mechanistic target of rapamycin pathway and associated with reduced glycolysis. 53 Consistently, dynamic transcriptomic and metabolic changes have been described in human peripheral blood cells during the first week after birth. In both murine enterocytes and blood monocytes, innate immune tolerance was associated with cellular reprogramming and expression of an alternative set of genes.…”

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

“…Examples include: (a) cholesterol, which participates in cell membrane remodeling and increased sensitivity to subsequent stimuli, (b) succinate and fumarate, which antagonize histone demethylation and suppress antiinflammatory genes, (c) acetyl-CoA, an essential substrate for acetylating processes, and (d) NAD + which is important for epigenetic changes resulting in a switch from glucose to fatty acid oxidation during LPS-induced tolerance and sepsis-induced immune paralysis (Conti et al, 2019). Immunometabolic changes may be different between newborns and adults, reflecting the differential nutritional and metabolic needs of the two groups, as well as their distinct immune response to pathogens (Kan et al, 2018;Dreschers et al, 2019). Indeed the ontogeny of immunometabolism is an emerging and promising area of research (Conti et al, 2019) (see Box 2).…”

Impaired functional capacity of polarised neonatal macrophages

“…We have previously shown that CBMФ exhibit reduced expression of phagocytosis receptors and cytokines in addition to altered energy metabolism. In particular, IFNy as well as IL10 activated CBMФ completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis 11 . Reduced polarisation capacity is likely to suppress MФ functions in neonates, such as activation and expansion of specialized T-cell subpopulations.…”

“…CD163, and Fc receptors, critically involved in phagocytosis of bacteria and cellular debris, i.e. elimination of haemoglobin-haptoglobin complexes (Hb:Hp), are overexpressed in MΦ-IL10 from adults (PBMΦ-IL10) but not in newborns (CBMΦ-IL10) 1,11 .…”