The phenotype and function of preterm infant monocytes: implications for susceptibility to infection

Abstract

The extreme vulnerability of preterm infants to invasive microbial infections has been attributed to "immature" innate immune defenses. Monocytes are important innate immune sentinel cells critical in the defense against infection in blood. They achieve this via diverse mechanisms that include pathogen recognition receptor- and inflammasome-mediated detection of microbes, migration into infected tissues, and differentiation into Mϕs and dendritic cells, initiation of the inflammatory cascade by free radicals and cytokine/chemokine production, pathogen clearance by phagocytosis and intracellular killing, and the removal of apoptotic cells. Relatively little is known about these cells in preterm infants, especially about how their phenotype adapts to changes in the microbial environment during the immediate postnatal period. Overall, preterm monocytes exhibit attenuated proinflammatory cytokine responses following stimulation by whole bacterial or specific microbial components in vitro. These attenuated cytokine responses cannot be explained by a lack of intracellular signaling events downstream of pattern recognition receptors. This hyporesponsiveness also contrasts with mature, term-like phagocytosis capabilities detectable even in the most premature infant. Finally, human data on the effects of fetal chorioamnionitis on monocyte biology are incomplete and inconsistent. In this review, we present an integrated view of human studies focused on monocyte functions in preterm infants. We discuss how a developmental immaturity of these cells may contribute to preterm infants' susceptibility to infections.

Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis

“…The lack of deficiencies in overall gene expression or cytokine production in monocytes from preterm chorioamnionitis‐unexposed infants compared to term infants was unexpected, as deficient monocyte responses to PRR‐stimulation in preterm infants are widely described . However, Lissner et al .…”

“…The lack of deficiencies in overall gene expression or cytokine production in monocytes from preterm chorioamnionitis-unexposed infants compared to term infants was unexpected, as deficient monocyte responses to PRR-stimulation in preterm infants are widely described. 6 However, Lissner et al also observed minimal transcriptional differences between purified monocytes from term infants and adults (following LPS or Listeria monocytogenes-stimulation), 16 despite reports of impaired monocyte-dependent cytokine responses to LPS in neonates compared to adults. 17,18 One possible mechanism is regulation of monocyte function through extrinsic factors either in cord plasma or from other mononuclear populations, which were removed in our experiments and those of Lissner et al A variety of soluble mediators capable of modulating monocyte responses are present in plasma, including adenosine, 19 the antimicrobial peptide LL-37 20,21 and the alarmins S100A8/A9.…”

“…Monocytes are central innate effector cells, and several phenotypic and functional characteristics of monocytes are impaired in preterm infants. 6 The primary monocyte deficit appears to be significantly reduced expression of inflammatory cytokines (TNFa, IL-1b, IL-6 and IL-8) at the protein level following TLR stimulation. However, preterm infant monocytes express comparable levels of important immune cell-surface receptors (e.g.…”

“…Newborn infants depend on innate immune defenses in the first weeks of life, prior to maturation of adaptive immune responses. Monocytes are central innate effector cells, and several phenotypic and functional characteristics of monocytes are impaired in preterm infants . The primary monocyte deficit appears to be significantly reduced expression of inflammatory cytokines (TNFα, IL‐1β, IL‐6 and IL‐8) at the protein level following TLR stimulation.…”

CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses

“…The critical nature of this period is exacerbated by Th 2 -skewed adaptive immunity [3, 4] and a reliance on transferred maternal antibodies [5], resulting in a dependence on innate immune mechanisms for protection [6, 7]. However, neonatal innate immune cells such as neutrophils [8–11], monocytes [12, 13], and dendritic cells [14] are also limited in their responses compared to adult cells. This immunosuppressed state has disadvantages such as predisposing newborns to severe infection and weakening their response to vaccination [2, 15].…”