Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages

Abstract

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 (MPhi) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, -4, and -9, neonatal MPhi make less proinflammatory cytokines and more IL-10 than adult MPhi. IL-10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal MPhi 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 MPhi. A microarray analysis of RNA from resting and LPS-stimulated MPhi 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 MPhi, although some cytokines, including IL-10 and IL-16, were enhanced. Several genes in the TLR signaling pathway leading to NF-kappaB activation were down-regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38alpha MAPK, known to be required for TLR-induced cytokine secretion, was enhanced in the neonatal MPhi. 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 Mphi may be unique to the developing organism, although it compromises the neonate's ability to respond to encapsulated bacteria.

Inhibition of IL-10 Production by Maternal Antibodies against Group B Streptococcus GAPDH Confers Immunity to Offspring by Favoring Neutrophil Recruitment

“…Absence of previous interactions with environmental microbes also implies that no immunological memory exists against specific antigens, which means that the acquired immune protection of newborns relies mainly on antibodies passively transferred from their mothers [40]. In addition, previous reports indicate that neonatal innate immune cells are less efficient in producing Th1-type inflammatory cytokines, but more competent in producing the immunosuppressive cytokine IL-10 upon Toll-like receptor (TLR) engagement by microbial products [41], [42], [43], [44]. Moreover, newborn mice leukocytes are highly committed to produce increased amounts of IL-10 [44], [45], as also shown in human neonates [41], [43], [46].…”

Role of Innate Host Defenses in Susceptibility to Early-Onset Neonatal Sepsis

“…Like monocytes, macrophages play an important role in the amplification of the immune response through the production of cytokines and chemokines, phagocytosis and killing, and antigen presentation to naïve CD4 + T cells. Neonatal macrophages are poorly responsive to several TLR agonists106 and IFN-γ94. During infection, neonatal macrophages exhibit decreased production of reactive nitrogen intermediates107.…”

Impaired Toll-like receptor 2 signalling in monocytes from 5-year-old allergic children

“…Age has shown to be of importance for innate immune responses in mice [20,21], making interpretations from different studies in humans difficult because of study populations with different ages. The immune system of the growing child is undergoing multiple important maturation steps.…”

“…An alternative explanation could be that the altered TLR regulation for allergic children in this study does not have an effect on the signalling pathway. A recent study in mice illustrates the complex interplay between TLR signalling and p38-MAPK activity when they show that an excess p38-MAPK activity can be inhibitory for TLR-induced production of proinflammatory cytokines [21].…”