Biology subjects

Villasenor, A.

Publications and source records attributed to Villasenor, A..

6 recordsLinked to original sources

bioRxiv2026

Mast cell desensitization induces a distinct IgE-dependent transcriptional program associated with immune regulation

Allergen-driven IgE-mast cell (MC) activation is a central feature of allergic diseases, whose prevalence continues to increase worldwide. Allergen immunotherapy (AIT) is currently the only disease-modifying treatment and induces a state of MC hyporesponsiveness termed desensitization; however, its underlying molecular mechanisms remain incompletely understood and whether this state reflects passive signal attenuation or active cellular reprogramming remains unresolved. Here, we define the molecular landscape of MC desensitization using a human polyclonal platform that captures the physiological diversity of allergen-specific IgE. Desensitization reduced degranulation in an allergen-specific manner and induced progressive internalization of allergen-specific IgE. Although early steps were associated with LAT phosphorylation, subsequent allergen challenge failed to propagate activation to distal IgE/Fc{varepsilon}RI effectors, revealing selective signaling uncoupling. Transcriptomic profiling uncovered a distinct transcriptional program comprising 168 upregulated genes enriched in immunoregulatory pathways and largely non-overlapping with classical activation signatures. This reprogramming occurred despite minimal alterations in mitochondrial respiration and selective impairment of allergen-induced glycolysis. Functionally, desensitized MCs enhanced allergen-driven proliferation of memory CD4 T cells. Together, these findings demonstrate that MC desensitization is not merely passive hyporesponsiveness but involves time-dependent allergen-specific IgE internalization, selective signal propagation, and a unique immunoregulatory transcriptional imprint that may contribute to tolerance during AIT.

immunology↗

bioRxiv2024

L-Phenylalanine is a metabolic checkpoint of human Th2 cells

After the primary response, circulating memory CD4+T effector and T regulatory cells (Treg) regulate recall responses, which are impaired in allergy. Using mass spectrometry, we discovered distinct metabolomes of these cells in humans and their unique enrichment in amino acids. By assessing energy metabolism in in vitro and ex vivo single-cell analyses, we determined that increased intracellular L-phenylalanine boosts glycolysis while limiting OXPHOS in CD4+T, memory CD4+T and Th2, but not in Treg cells. L-phenylalanine also restrains memory CD4+T proliferation in an IL4I1-dependent manner and inhibits Th2 cell proliferation and differentiation. RNA-sequencing, metabolomics, flow cytometry and proteomics, validated in vitro and across patients cohorts, revealed an impairment in LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy with an increase in its intracellular processing, accompanied by an expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in the development, energy metabolism and function of Th2 cells.

immunology↗

bioRxiv2023

Allergic inflammation triggers dyslipidemia via IgG signalling

BackgroundAllergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. MethodsWe used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TG) were evaluated in a group of 59 patients [≥]14 days after the onset of an allergic reaction. ResultsWe found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TG and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TG in 59 patients after undergoing an allergic reaction. ConclusionOverall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

immunology↗

bioRxiv2023

Pentose Phosphate Pathway Inhibition activates Macrophages towards phagocytic Lymphoma Cell Clearance

Macrophages in the B-cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition by specific compounds and shRNA targeting induced increased phagocytic lymphoma cell clearance. Moreover, macrophages provided decreased support for survival of lymphoma cells. PPP inhibition induced metabolic activation, cytoskeletal re-modelling and pro-inflammatory polarization of macrophages. A link between PPP and immune regulation was identified as mechanism of macrophage repolarization. Inhibition of the PPP causes suppression of glycogen synthesis and subsequent modulation of the immune modulatory UDPG-Stat1-Irg1-Itaconate axis. PPP inhibition rewired macrophage maturation and activation in vivo. Addition of the PPP inhibitor S3 to antibody therapy achieved significantly prolonged overall survival in an aggressive B-cell lymphoma mouse model. We hypothesize the PPP as key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies. HighlightsO_LIMacrophage-mediated lymphoma cell phagocytosis is increased by pentose phosphate pathway (PPP) inhibition as an immune regulatory switch for macrophage function and polarization C_LIO_LIPPP inhibition is linked to decreased glycogen synthesis and subsequent modulation of the UDPG-Stat1-Irg1-Itaconate axis C_LIO_LIPPP inhibition is tolerable in vivo and facilitates therapeutic targeting of B-cell lymphoma C_LI

cancer biology↗

bioRxiv2021

Regenerating insulin-producing β-cells ectopically from a mesodermal origin in the absence of endothelial specification

To investigate the role of the vasculature in pancreatic {beta}-cell regeneration, we crossed a zebrafish {beta}-cell ablation model into the avascular npas4l mutant (i.e. cloche). Surprisingly, {beta}-cell regeneration increased markedly in npas4l mutants owing to the ectopic differentiation of {beta}-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic {beta}-cells expressed endocrine markers of pancreatic {beta}-cells, and also reduced glucose levels in the {beta}-cell ablation model. Through lineage tracing, we determined that the vast majority of these ectopic {beta}-cells derived from the mesodermal lineage. Notably, ectopic {beta}-cells were found in npas4l mutants as well as following knockdown of the endothelial determinant Etv2. Together, these data indicate that in the absence of endothelial specification, mesodermal cells possess a remarkable plasticity enabling them to form {beta}-cells, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for {beta}-cell regeneration.

developmental biology↗

bioRxiv2018

Hhex regulates the specification and growth of the hepatopancreatic ductal system

Significant efforts have advanced our understanding of foregut-derived organ development; however, little is known about the molecular mechanisms that underlie the formation of the hepatopancreatic ductal (HPD) system. Here, we report a role for the homeodomain transcription factor Hhex in directing HPD progenitor specification in zebrafish. Loss of Hhex function results in impaired HPD system formation. We found that Hhex specifies a distinct population of HPD progenitors that gives rise to the cystic duct, common bile duct, and extra-pancreatic duct. Since hhex is not uniquely expressed in the HPD region but is also expressed in endothelial cells and the yolk syncytial layer (YSL), we tested the role of blood vessels as well as the YSL in HPD formation. We found that blood vessels are required for HPD patterning, but not for HPD progenitor specification. In addition, we found that Hhex is required in both the endoderm and the YSL for HPD development. Our results shed light on the mechanisms necessary to direct endodermal progenitors towards the HPD fate and also advance our understanding of HPD system formation.

developmental biology↗