Winters, H. | bioRxiv Science

bioRxiv2026

Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

Background & AimsUnchecked inflammation in Eosinophilic esophagitis (EoE) leads to esophageal fibrosis and eventual stricture. Differentiated fibroblasts, termed myofibroblasts, are the main effector cells in fibrosis, responsible for secreting extracellular matrix proteins leading to tissue stiffness. Regulating myofibroblasts has not been explored as a therapeutic possibility in the fibrostenotic esophagus. Herein, we aim to investigate the efficacy of Prostaglandin E2 (PGE2) in dedifferentiation of the EoE myofibroblast. MethodsWe evaluated the efficacy and mechanism of myofibroblast dedifferentiation using fetal esophageal fibroblasts (FEF3), patient-derived fibroblasts, and a murine model of EoE. ResultsFibrosis markers (SMA, FN1, and COL1A1) and contractility of myofibroblasts were significantly decreased by PGE2 via the cAMP pathway. PGE2 treatment decreased nuclear accumulation of phospho-Smad2/3-YAP complex and induced phospho-YAP proteasomal degradation. Transcriptome analyses of FEF3 treated with TGF{beta} or PGE2 revealed that the Integrin1 pathway, and specifically thrombospondin 1 (THBS-1), was significantly upregulated by TGF{beta} and downregulated by PGE2, as supported by pseudo-bulk single-cell RNA-seq of EoE biopsies. THBS-1 was shown to be regulated by PGE2 via the cAMP/YAP pathway, and its knockdown induced myofibroblasts dedifferentiation. In a murine model of EoE, Butaprost, agonist of the E-prostanoid G protein-coupled receptor 2, treatment significantly reduced the expression of THBS-1, SMA, and FN1 along with a decrease in YAP nuclear translocation. Additionally, collagen fiber organization in the lamina propria was markedly reduced. ConclusionPGE2 promotes dedifferentiation of myofibroblasts in EoE via the cAMP/YAP/ THBS-1 pathway. Our data suggest that PGE2 is a promising treatment strategy for EoE with stenosis. What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSIn Eosinophilic esophagitis, unchecked inflammation and tissue stiffness drives fibroblast differentiation and fibrostenosis of the esophagus, yet targeting myofibroblasts as regulators of extracellular matrix deposition in fibrostenotic disease remains clinically unexplored. New FindingsProstaglandin E2 promotes dedifferentiation of myofibroblasts in eosinophilic esophagitis via the cAMP/YAP pathway, with Thrombospondin-1 identified as a critical YAP regulated target driving fibrostenosis. LimitationsThis study focused on fibroblast-specific mechanisms. The effects of PGE2 on esophageal epithelial differentiation, barrier function, and immune cell recruitment in EoE remain to be determined. Clinical Research RelevanceThis study demonstrates proof-of-concept that pharmacological reversal of established fibrosis is achievable in EoE. PGE2 and its EP2-selective agonists represent translatable therapeutic targets for fibrostenotic EoE--a patient population that remains treatment-refractory to current immunosuppressive approaches. Basic Research RelevanceThe cAMP/YAP/THBS-1 signaling in fibroblasts emerges as a critical therapeutic target for esophageal fibrosis. Importantly, this work demonstrates that terminally differentiated myofibroblasts retain remarkable plasticity and can dedifferentiate--challenging the paradigm that fibrosis is irreversible.

cell biology↗

bioRxiv2025

Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism

Type 2 cytokine release promotes wound healing and helminth clearance, but it remains unclear whether group 2 innate lymphocytes (ILC2s) and T-helper 2 cells (TH2) cells have functionally distinct roles during anamnestic immunity. This study demonstrates that ILC2 can block re-infection and limit tissue injury caused by the helminth Nippostrongylus brasiliensis (Nb). TH2 cells were necessary during initial antigen encounter but dispensable for pathogen clearance and lung repair after ILC2 priming. Upon re-infection, trained ILC2 selectively blocked interleukin (IL)-17+ {gamma}{delta}T cell expansion and infection-induced lung injury through an Amphiregulin (Areg)-independent mechanism. Trained ILC2s had a distinct metabolic gene expression profile marked by elevated tryptophan hydroxylase 1(Tph1) and pulmonary serotonin levels were largely ILC2-dependent. Surprisingly, serotonin prevented IL-17-associated lung hemorrhage irrespective of parasite load. We propose that TH2-ILC2 interactions drive pathogen control, but ILC2 distinctly control lung tissue repair through serotonin.

immunology↗

bioRxiv2025

Plant host identity drives Andropogon gerardii rhizobiome assembly strategies under increasing abiotic stress

Predicted changes in precipitation threaten tallgrass prairies by altering the soil microbial communities that are essential for plant resilience. Andropogon gerardii, a dominant grass in tallgrass prairies, spans the contiguous North American precipitation gradient. However, it remains unclear to what extent the rhizosphere microbiomes (rhizobiomes) are influenced by the plant-host environmental interaction. To assess how environmental and host factors shape the rhizobiome, we surveyed A. gerardii populations across 25 remnant prairie sites (June-August 2023) within its native range in the United States, characterizing the microbiomes in the rhizosphere and soils using 16S amplicon sequencing. We demonstrated that while geographic location largely structured both rhizosphere and soil communities, regional precipitation (60-day rainfall) emerged as a primary driver of the microbial community assembly. We observed distinct microbial divides across the dry and wet regions of the North American "arid-humid divide." Importantly, we found the first compelling large-scale evidence that regional precipitation has a profound influence on rhizobiome assembly. In the most arid regions, rhizosphere microbial communities exhibited significantly more predicted stochasticity than those in the local soil and contained taxa related to host-benefiting functions. Our study suggests that intensified host-driven selection for specific microbial variants occurs under heightened abiotic stress, highlighting the hosts pivotal role in shaping its rhizobiome composition in challenging environments.

microbiology↗