New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease

Abstract

It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This is highly important because neonates are immunologically challenged directly after birth by a rigorous change from a semi-allogeneic sterile environment into a world rich with microbes. A so called disease tolerogenic state is typical for neonates and is anticipated to prevent immunopathological damage potentially at the cost of uncontrolled pathogen proliferation. As a consequence, neonates are more susceptible than adults to life-threatening infections. At the basis of a well-functioning immune response, both for adults and neonates, innate immune cells such as monocytes and monocyte-derived macrophages play an essential role. A well-responsive monocyte will alter its cellular metabolism to subsequently induce certain immune effector function, a process which is called immunometabolism. Immunometabolism has received extensive attention in the last decade; however, it has not been broadly studied in neonates. This review focuses on carbohydrate metabolism in monocytes and macrophages in neonates. We will exhibit pathways involving glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and their role in shaping neonates' immune systems to a favorable tolerogenic state. More insight into these pathways will elucidate potential treatments targets in life-threatening conditions including neonatal sepsis or expose potential targets which can be used to induce tolerance in conditions where tolerance is harmfully impaired such as in autoimmune diseases.

Keywords: bacterial; commensals; neonatal infection; neonatal tolerance.

Figure 1

Differences in carbohydrate metabolism between adult and neonatal monocytes/macrophages. Red-circled arrows indicate immunometabolic differences in neonates in relation to adults. In neonatal mononuclear phagocytic cells (monocytes and macrophages), GLUT1 and phosphofructokinase M (PFKM) mRNA are reduced. In line with this, a consecutive reduction in glycolysis activity leads to a lower expression of MALT1 signalosome genes, which are induced after pattern recognition receptors (PAMPS) activation. Consequently, pro-inflammatory cytokine production in neonates is reduced and the expression of the costimulatory molecules CD80 and CD86 is abrogated leading to impaired induction of T cell proliferation upon LPS stimulation. Regarding the TCA cycle, MPC1 and MPC2 gene expression is reduced. The MPC1/MPC2 heterodimer translocates pyruvate from the cytosol to the mitochondria. In addition, the gene expression of the enzymes pyruvate carboxylase (PC) and malate dehydrogenase 2 (MDH2) is downregulated, impairing the processing of pyruvate to oxaloacetate and malate to oxaloacetate, respectively.

Figure 2

Factors dictating immunometabolism in neonates. Red-circled arrows indicate immunometabolic differences in neonates in relation to adults. In breast milk, fecal samples and serum of neonates the antimicrobial proteins S100A8 and S100A9 (forming a heterodimer) are upregulated. S100 proteins diminish glycolysis and subsequently inflammation induced by pathogens. This is (at least partly) regulated by mTOR. In neonates, mTOR phosphorylation (p-mTOR) was reduced. Subsequently, suppression of p-mTOR activation leads to reduced glycolysis activity. In addition, S100A8 and S100A9 induce immune responsiveness via MyD88-dependent genes. Furthermore, epigenetic alternations were observed in preterm neonates compared to term neonates; however, it has not been studied to date how carbohydrate metabolism is affected by this. Unsolved questions with respect to glycolysis are depicted with a question mark. Furthermore, miRNA-146 (both miRNA-146a and b) is upregulated in human neonatal monocytes. Altogether, these differences lead to an immune system that is primed to induce disease tolerance instead of disease resistance.