Abstract
Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring.
Highlights
CSF1-independent macrophages were still found in adult spiral ganglion, but were not sufficient to support healthy cochlear development [117]. While these findings provide the first line of evidence that fetal-derived tissue-resident macrophages are important for cochlear development and hearing function, the specific contribution of distinct fetal macrophage subsets to cochlear development, function, homeostasis, and response to perturbation requires further investigation
As hematopoietic stem cells are sensitive to inflammation [54], perinatal inflammation could have a potent impact on the development, function, and composition of developing hematopoietic stem cells, and thereby alter the trajectory of immune output
We propose that the developing cochlea is an ideal system to directly examine how perinatal infection and inflammation drives disease pathogenesis
Summary
The last three decades have witnessed a significant shift in understanding of how early microbe exposure influences lifelong health outcomes. The term “perinatal” encompasses both fetal as well early postnatal development, and captures continuity of development and continuity of inflammation or exposure that occurs across this developmental window. Underlying these changes is the notion that the developing immune system must be “programmed” at some level by inflammation [19]. Based on advancements in understanding of both hematopoietic and immune development over the last decade, we posit at least two probable mechanisms by which perinatal inflammation could influence long-term immune outcomes in offspring: first, by perturbing the development and function of fetal-derived immune cells, and second, by perturbing the establishment and function of developing hematopoietic stem cells (Figure 1). On tissue immunity and/or the output of the hematopoietic system
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