Molecular mechanisms underlying anti‐inflammatory phenotype of neonatal splenic macrophages

Neonatal humans and rodents are susceptible to infection with encapsulated bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines by splenic macrophages (MΦ) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, ‐4, and ‐9, neonatal MΦ make less proinflammatory cytokines and more IL‐10 than adult MΦ. IL‐10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal MΦ treated with anti‐IL‐10 receptor antibody or from IL‐10 –/– mice produced levels of proinflammatory cytokines at a level comparable with that produced by adult MΦ. A microarray analysis of RNA from resting and LPS‐stimulated MΦ from neonatal and adult mice showed that expression of a large number of genes encoding cytokines, chemokines, and their receptors was decreased dramatically in the neonatal MΦ, although some cytokines, including IL‐10 and IL‐16, were enhanced. Several genes in the TLR signaling pathway leading to NF‐κB activation were down‐regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38α MAPK, known to be required for TLR‐induced cytokine secretion, was enhanced in the neonatal MΦ. Our studies with the p38 MAPK inhibitor SB203580 suggested that excess p38 MAPK activity can be inhibitory for TLR2‐, ‐4‐, and ‐9‐induced production of proinflammatory cytokines but not IL‐10. The anti‐inflammatory phenotype of the neonatal Mφ may be unique to the developing organism, although it compromises the neonate’s ability to respond to encapsulated bacteria.