Scientists show that prenatal stress reshapes fetal mast cells and sensory neurons, creating a fragile skin barrier that sparks early-life eczema in mice.
Study: Maternal stress triggers early-life eczema through fetal mast cell programming. Image Credit: Prostock-studio / Shutterstock
A recent study revealed that maternal stress triggers early-life eczema in mice through fetal mast cell programming. Prenatal stress (PS) is repeated exposure to aversive situations in pregnancy, including emotional strain. PS is suspected to impact infant homeostatic systems. Pediatric eczema typically develops rapidly after birth, often at flexural sites that are subjected to mechanical stress. While epidemiological studies suggest an association between PS and a higher risk of eczema in children, causal links have yet to be determined, and the findings of this study remain preclinical.
The study and findings
The present study showed that maternal stress induces early-life eczema through corticosterone-driven dysregulation of fetal skin mast cells and sensory neurons. First, the researchers used a PS mouse model to study the effects of PS on atopic dermatitis at birth. Pregnant dams were exposed to bright light for 30 minutes thrice a day from embryonic day 13 (E13) to E18. The PS procedure did not affect the weight of pregnant dams or the weight and litter size of the offspring. The skin of eight-week-old (W8) PS and control offspring was histologically and visually comparable.
Nevertheless, high trans-epidermal water loss was observed at steady state in W3 and W8 offspring, an indicator of a loose barrier in atopic dermatitis. Furthermore, W8 offspring serum showed elevated levels of interleukin 5 (IL-5), 7 (IL-7), and 9 (IL-9), as well as CXC motif chemokine ligand 9 (CXCL9). The researchers also detected a mixed immune signature that included type 1, type 2, type 17, and regulatory responses. Next, the team developed a soft mechanical skin damage model by tape stripping. This did not trigger inflammation in control offspring.
Conversely, W3 and W8 PS offspring developed eczematous lesions, characterized by pronounced inflammation and a mixed immune signature (including type 1, 2, and 17 responses) typical of pediatric eczema. Further, W8 offspring were subjected to a light, continuous wet friction to mimic wet flexural sites. While W8 control offspring showed no inflammation, PS offspring developed severe lesions. These data indicated that the PS model was associated with the development of eczema-like lesions in offspring in response to innocuous mechanical friction.
The lesions were distinct from adult atopic dermatitis and naturally resolved with age by week 24 (W24). In addition, W8 PS offspring showed significantly increased somatic mechanical sensitivity compared to controls, driven by transcriptomic and anatomical changes in non-peptidergic and c-LTMR sensory neurons. Next, CD45+ immune cells were isolated from the skin of W8 and W24 offspring and subjected to single-cell RNA sequencing (scRNA-seq). Skin mast cells in PS offspring showed the most modifications with 530 DEGs and chromatin accessibility remodeling that represented transient epigenomic alterations, which normalized by W24.
Many DEGs in skin mast cells of PS offspring were genes involved in granule formation/trafficking, stress-response pathways, and cell metabolism/activation. Moreover, PS skin mast cells were already highly degranulated/activated at steady state. Next, the team assessed the role of mast cells in eczematous lesions in response to light, continuous wet friction. To this end, two transgenic, mast cell-deficient mouse models were used.
One mouse model (Mcpt5-cre; Dta) selectively lacked most skin mast cells, while the other (KitWsh/Wsh) had abnormalities in addition to mast cell deficiency. Both models were almost entirely protected from eczematous lesions associated with PS. Notably, sensory neuron alterations persisted in protected mice, indicating the existence of independent pathways for inflammation and mechanical hypersensitivity. Next, the team assessed whether PS impacts fetal skin mast cell programming in utero. Although the number and distribution of mast cells remained unchanged at E18.5, mast cells in PS fetal skin were already highly degranulated.
Moreover, most degranulated mast cells were yolk sac-derived at E18.5, while a minority of cells originated from hematopoietic stem cells. Further, most mast cells at W8 were of yolk sac origin, which became undetectable by W24, explaining the natural resolution of symptoms. Environmental stress in pregnancy could activate stress response systems, including the sympathetic-adrenal-medullary (SAM) and hypothalamic-pituitary-adrenal (HPA) axes.
As such, the team assessed whether embryonic sensory neurons or mast cells expressed the β2-adrenergic receptor, adrenoceptor beta 2 (Adrb2), or the glucocorticoid receptor, nuclear receptor subfamily 3 group C member 1 (Nr3c1), during development, integrating signals from the SAM and HPA axes, respectively.
Using public scRNA-seq datasets of mouse DRG and skin development, the researchers found that sensory neurons expressed high levels of Nr3c1 but not Adrb2 during development. Furthermore, at E13.5, skin macrophages expressed Adrb2, whereas skin mast cells expressed high levels of Nr3c1 but not Adrb2, confirming the specificity of glucocorticoid signaling. Next, the team examined corticosterone levels at the maternal-fetal interface, as fetal skin is directly in contact with amniotic fluid.
Corticosterone levels were elevated in the amniotic fluid and blood of stressed dams, but this increase was not evident in embryos at E18.5 or after birth. Fetal skin mast cells at E18.5 were monitored for degranulation dynamics in response to various stimuli. Corticosterone addition significantly increased the mean fluorescence intensity, indicating it can act directly on fetal mast cell activation.
Moreover, corticosterone-enriched amniotic fluid from PS yolk sacs induced fetal skin mast cell degranulation, while that from control yolk sacs did not. Further, to assess the role of corticosterone in PS-associated eczematous lesions, the team developed a protocol involving repeated intraperitoneal metyrapone injection before each stress session to normalize corticosterone levels in stressed pregnant dams.
Metyrapone selectively inhibits cytochrome P450 family 11 subfamily B member 1 (CYP11B1), which is responsible for the synthesis of corticosterone. This protocol inhibited corticosterone spikes triggered by PS and did not affect the weight of pregnant dams or their offspring. It also did not reduce cytokine levels found in the amniotic fluid post-PS, indicating that the induction of a pro-inflammatory environment was independent of corticosterone.
Notably, W8 PS offspring born from metyrapone-treated dams were almost entirely protected from eczematous lesions upon mild continuous wet friction. This protocol also prevented abnormal mast cell activation programs in E18.5 fetal and W8 adult skin. The amniotic fluid of metyrapone-treated dams did not activate fetal mast cells in vitro, confirming that corticosterone, not inflammatory cytokines, drives fetal mast cell activation.
Translational relevance: Human fetal sensory neurons and skin mast cells expressed high NR3C1 levels similarly, and atopic pregnant women showed elevated early-gestation cortisol levels, validating the mouse findings. However, causality in humans has not been established, and further research is required.
Conclusions
In sum, sensory and inflammatory features of early-onset pediatric eczema stem from in utero molecular dysregulations of immune and neuronal compartments induced by fluctuations in the maternal HPA axis.
The findings reveal that fetal skin mast cells play a critical role in the development of eczematous lesions at birth. This "fragilized" neonatal skin barrier could predispose infants to the "atopic march" (progression to food allergies/asthma). However, this proposed progression remains speculative and was not directly demonstrated in the study.
Overall, a deeper understanding of the equilibrium at the maternal-fetal interface could aid in the development of interventions to mitigate the impact of environmental factors during pregnancy.