Biology subjects

Rehli, M.

Publications and source records attributed to Rehli, M..

5 recordsLinked to original sources

bioRxiv2026

Timed STING Inhibition Mitigates Gastrointestinal GvHD While Preserving Graft-versus-Leukemia Activity After Allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for hematological malignancies but limited by graft-versus-host disease (GvHD), in which donor T cells damage host tissues. Current prophylaxis broadly suppresses donor immunity, often compromising the beneficial graft-versus-leukemia (GvL) response, highlighting the need for strategies that uncouple GvHD from GvL. The cGAS-STING pathway can be strongly activated during conditioning-induced tissue damage and represents a potential therapeutic target. However, its context-dependent roles in inflammation and homeostasis have constrained its clinical translation. Here, we show that "timed" administration of the covalent STING inhibitor H151 before conditioning reduced GvHD-associated mortality without impairing GvL in murine allo-BMT models. Donor T cell activation and effector function were preserved, indicating that the protective effect operates at the level of GvHD target tissues rather than through systemic immunosuppression. Timed STING inhibition protected the intestinal epithelium by limiting apoptosis, preserving intestinal stem cell function, and sustaining metabolic fitness during conditioning-induced injury, independently of type I interferon (IFN-I) signaling. In allo-HSCT patients, low intestinal STING expression is associated with reduced transplant-related mortality. Together, these findings identify timed STING inhibition as a tissue-protective prophylactic strategy that could be incorporated into existing conditioning regimens to enhance efficacy while minimizing toxicity.

immunology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2024

Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury

Intestinal stem cells (ISC) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses such as interferon-{gamma} (IFN{gamma})-mediated killing. In mouse models of gut damage and biopsies from patients having undergone allo-hematopoietic stem cell transplantation, we observed IFNy expression by intestinal Treg cells. Treg cells leverage combined IFN{gamma} and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, Treg cells or the combined addition of recombinant IFN{gamma} and IL-10 promote the regeneration of organoids after irradiation. Exposure of organoids to Wnt- or EGF-free culture conditions revealed distinct growth factor-like properties of IFN{gamma} and IL-10. While IFN{gamma} induced epithelial proliferation and differentiation, combined addition of IFN{gamma} and IL-10 led to balanced proliferation, ensuring ISC maintenance. Our results uncover a context-dependent role of inflammatory signaling in ISC, through which Treg cells promote epithelial repair.

immunology↗

bioRxiv2023

Darwin's "neuters" and the evolution of the sex continuum in a superorganism

Ant castes are an amazing example of phenotypic plasticity. In worker-destined embryos of the ant Cardiocondyla obscurior, the default female developmental trajectory is interrupted even before the gonadal precursor cells acquire a sexual identity. miRNA and mRNA expression in embryos reveal three distinct phenotypic entities: males, females, and "neuters", as Darwin coined the worker caste in "On the Origin of Species". Based on these results we propose that haplodiploidy, in conjunction with insect sex determination, allows for the expression of a third dimension on the sex continuum, thus facilitating the evolution of individuals which develop traits their parents do not have. One sentence summarySex and caste differentiation begin during the same embryonic developmental window in the ant Cardiocondyla obscurior.

evolutionary biology↗

bioRxiv2016

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share patterns of transcriptional regulation. Accordingly, shared transcriptional regulation (coexpression) may help prioritise loci associated with a given trait, and help to identify the biological processes underlying it. Using cap analysis of gene expression (CAGE) profiles of promoter and enhancer-derived RNAs across 1824 human samples, we have quantified coexpression of RNAs originating from trait-associated regulatory regions using a novel analytical method (network density analysis; NDA). For most traits studied, sequence variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. These networks implicate particular cell types and tissues in disease pathogenesis; for example, variants associated with ulcerative colitis are linked to expression in gut tissue, whereas Crohns disease variants are restricted to immune cells. We show that this coexpression signal provides additional independent information for fine mapping likely causative variants. This approach identifies additional genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. This approach enables a deeper biological understanding of the causal basis of complex traits.\n\nONE SENTENCE SUMMARYWe discover that variants associated with a specific disease share expression profiles across tissues and cell types, enabling fine mapping and identification of new disease-associated variants, illuminating key cell types involved in disease pathogenesis.

genomics↗