Edited by: Vassiliki Papaevangelou, National and Kapodistrian University of Athens, Greece
Reviewed by: Riccardo Castagnoli, University of Pavia, Italy; Stefan Winkler, Dresden University of Technology, Germany
This article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
During early post-natal life, neonates must adjust to the transition from the sheltered intra-uterine environment to the microbe-laden external world, wherein they encounter a constellation of antigens and the colonization by the microbiome. At this vulnerable stage, neonatal immune responses are considered immature and present significant differences to those of adults. Pertinent to innate immunity, functional and quantitative deficiencies in antigen-presenting cells and phagocytes are often documented. Exposure to environmental antigens and microbial colonization is associated with epigenetic immune cell reprogramming and activation of effector and regulatory mechanisms that ensure age-depended immune system maturation and prevention of tissue damage. Moreover, neonatal innate immune memory has emerged as a critical mechanism providing protection against infectious agents. Still, in neonates, inexperience to antigenic exposure, along with enhancement of tissue-protective immunosuppressive mechanisms are often associated with severe immunopathological conditions, including sepsis and neurodevelopmental disorders. Despite significant advances in the field, adequate vaccination in newborns is still in its infancy due to elemental restrictions associated also with defective immune responses. In this review, we provide an overview of neonatal innate immune cells, highlighting phenotypic and functional disparities with their adult counterparts. We also discuss the effects of epigenetic modifications and microbial colonization on the regulation of neonatal immunity. A recent update on mechanisms underlying dysregulated neonatal innate immunity and linked infectious and neurodevelopmental diseases is provided. Understanding of the mechanisms that augment innate immune responsiveness in neonates may facilitate the development of improved vaccination protocols that can protect against pathogens and organ damage.
During early life, newborns encounter a plethora of antigenic challenges derived from pathogens, commensals, and innocuous environmental antigens (
In this review, we present the most recent advances in the characterization of the phenotype and functions of neonatal innate immune cells, outlining the disparities with adult responses. Given that there is limited space to delve into the extensive series of animal studies, we focus on reports on human cells. In addition, we provide an overview of the effects of the microbiome, the metabolome, and epigenetics on the regulation of neonatal innate immunity. The immunological mechanisms underlying infections, brain injury, and neurodevelopmental disorders are also presented. Finally, we discuss future research directions that may boost neonatal host defense through targeting innate immune responses.
Human dendritic cells (DCs) mainly consist of two developmentally-distinct lineages; conventional (cDCs) that induce T cell activation and differentiation, and plasmacytoid DCs (pDCs), which produce type I interferons and mediate anti-viral responses (
Monocytes play a key role in pathogen recognition and eradication through their phagocytic, antigen-presenting and cytokine-secreting abilities. Neonatal monocytes express decreased levels of HLA-DR and CD80, leading to impaired presentation of antigens, including pathogen-derived molecules (
Compared to their adult counterparts, neonatal macrophages have increased cytoplasmic vacuolization and reduced expression of lipid residues, CD11b, CD14, and F4/80 (
Overall, these studies highlight impaired antigen-presenting functions, cytokine secretion and T cell stimulatory abilities of neonatal DCs and monocytes/macrophages upon pathogen encounter, a phenomenon that renders neonates particularly vulnerable to infections (
Innate immune responses in neonates. The quantitative and functional characteristics of neonatal innate immune responses are depicted and compared to those of adults. These features of innate immune cells render newborns vulnerable to severe infections and organ damage.
Neutrophils provide the first line of defense against pathogens through phagocytosis, release of toxic substances and generation of neutrophil extracellular traps (NETs). Neonatal neutrophils exhibit impaired rolling and adhesion capabilities, resulting from decreased expression of L-selectin, CD11b/CD18, and P-selectin glycoprotein ligand-1 (
NK cells protect against pathogens through cytokine release and killing of infected cells. Expression of a complex repertoire of activating (CD94/NKG2C, killer immunoglobulin-like 1 receptor) and inhibitory receptors (CD94/NKG2A) enables NKs to sense infected and/or transformed cells (
Innate Lymphoid Cells (ILCs) are characterized by the release of Th cell-associated cytokines and the absence of antigen-specific receptors. ILCs are classified into three subgroups (ILC1, ILC2, ILC3), based on their cytokine and transcription factor profile and represent essential drivers of early host responses during infection and injury (
Epigenetic modifications, including acetylation, methylation, ubiquitination, phosphorylation and sumoylation on histones, and/or DNA, as well as, microRNA-mediated regulation of translation have a major impact on innate immunity. Studies conducted during the post-natal period have shown a decrease of the histone mark H3K4me1 in monocytes, concomitant with a gradual increase of the H3K4me3 mark, mostly at promoter regions (
The microbiome plays a catalytic role in the maturation of neonatal immune responses. In fact, only during juvenility, wherein the microbiome shifts to the adult composition, the establishment of a fully-operating immune system occurs (
Experimental studies using germ-free mice demonstrated that the microbiome affects macrophage development and polarization, granulocyte numbers and haematopoiesis during early life (
Collectively, the aforementioned studies suggest that epigenetic alterations and the microbiome composition greatly affect neonatal innate immune responses; however, the precise immunological and molecular mechanisms involved remained incompletely explored. Further animal studies and
The past years, there is an increasing interest in the analysis of the metabolome of biological fluids, including the amniotic fluid, the cord and the peripheral blood, the saliva, and the urine in newborns (
The interdependency of the microbiome, diet and the metabolome is exemplified by the colonization of the neonatal intestine early-on during development by the
Dysregulated innate immune responses render newborns susceptible to severe infections. Neonatal sepsis occurs predominantly in response to respiratory tract infections and meningitis, and represents a major cause of morbidity and mortality in the neonatal period, especially in very low birth-weight preterm infants (
Accumulating evidence illuminates critical defects of neonatal innate immunity during sepsis. Septic neonates present deficiencies in the recognition of pathogen products, including LPS, and in TNF-α, IFN-γ, IL-12 release that stem on TLR (especially TLR4) defects and reduced intracellular signaling by myeloid differentiation primary response protein 88 and MAPK p38 [(
Dysregulated neuro-immune communication underlies the pathology of infections and CNS disorders in neonates. Infections, such as chorioamnionitis, dermatitis, meningitis, necrotizing enterocolitis, and respiratory infections, can lead to systemic inflammation and severe sepsis in newborns. Pathogen associated molecular patterns (PAMPs), generated during infections, are recognized via PRRs by innate immune cells and this induces cell activation and the production of pro-inflammatory mediators in the periphery and the CNS. On the other hand, maternal infections during pregnancy and/or EOS, and intrapartum asphyxia can induce brain injury and HIE, respectively, and further activate innate immune responses. Dysregulated neuro-immune communications underlie the pathogenesis of systemic infections and brain damage in neonates and may lead to neurodevelopmental and neuropsychiatric disorders.
Strikingly, neonates can also exhibit exaggerated innate immune responses that may lead to severe organ damage. Indeed, systemic inflammation during neonatal infections is closely linked to brain injury and neurological impairments (
Several molecules involved in innate immunity, including cytokines, the complement cascade and adhesion molecules, are expressed in the healthy brain wherein they play essential roles in neurogenesis, migration, differentiation, synapse formation, and plasticity (
Intrapartum asphyxia causes hypoxia-ischemia (HI) which induces long-term neurological disorders, including cerebral palsy, visual impairment, seizures, epilepsy, mental retardation, and learning disabilities (
Autism spectrum disorders (ASD), Alzheimer's disease, major depression and schizophrenia, are considered as closely linked to three interrelated mechanisms; (a) dysregulated neuro-immune communication, (b) dysbiosis of the gut microbiome, and (c) early-life infections (
It is becoming increasingly clear that the development of immune responses in neonates is compromised not only as a result of immaturity but also as an attempt to maintain tolerance to innocuous and commensal antigens and prevent tissue damage. Still, once neonatal immune responses are activated, their magnitude is often such that they can cause severe immune pathology and morbidity, especially during infections and HI (
Intricate interactions between the microbiome and the nervous and the immune systems affect neonatal responses during infections and brain injury. As such, alterations in the microbial composition, for example through dietary supplementation, may modulate key pathways of neuroimmune communication and enhance regulatory mechanisms that prevent neuronal damage. Interventions, including corticosteroids, melatonin, erythropoietin, anti-TNF-α antibodies, and IL-1rα administration, in clinical use for other diseases, may be also utilized for the control of neurological disorders in susceptible neonates (
GT and PN searched the literature and wrote the manuscript. GT designed the figures. GX contributed to critical revision of the article, suggested additional references, and wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
dendritic cells
conventional dendritic cells
plasmacytoid dendritic cells
lipopolysaccharide
T helper type 1
pattern recognition receptors
Toll-like receptor
cytosine-phosphate-guanosine
polyinosinic-polycytidylic acid
peptidoglycan
herpes simplex virus
human leukocyte antigen-DR isotype
B-cell lymphoma 2
mitogen-activated protein kinase
nucleotide-binding domain and leucine-rich repeat containing protein 3
neutrophil extracellular traps
natural killer
Innate Lymphoid Cells
necrotizing enterocolitis
early-onset sepsis
late-onset sepsis
hypoxia-ischemia
hypoxic-ischemic encephalopathy
cerebrospinal fluid
autism spectrum disorders.