Biology subjects

Tersey, S. A.

Publications and source records attributed to Tersey, S. A..

10 recordsLinked to original sources

bioRxiv2026

Microbiome histidine competition mediates dietary control of systemic imidazole propionate

The gut microbiome produces numerous metabolites that influence mammalian health. While microbiome composition and diet influence metabolite concentrations, how these factors interact remains incompletely defined. Here we find production of imidazole propionate (ImP), a microbial metabolite associated with cardiometabolic and neurodegenerative diseases, is determined by the balance of competing metabolic pathways that catabolize histidine to ImP or short-chain fatty acids (SCFAs). We show glutamate serves as a preferred substrate that selectively inhibits histidine conversion to SCFAs, redirecting flux to increased ImP production across mouse- and human-derived microbial communities. We find dietary monosodium glutamate (MSG) acting via this mechanism boosts ImP production in the mouse gut, transiently impairing glucose tolerance and increasing systemic ImP. These findings show that predictable interactions between dietary substrate and microbial competition control systemic ImP levels, providing a mechanistic framework for understanding microbiome metabolite production more broadly.

microbiology↗

bioRxiv2025

Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility

Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet {beta} cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibit a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse {beta} cells with the sex hormone 17{beta}-estradiol (E2) suppressed inflammatory signaling and markers of {beta}-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduces diabetes incidence and limits progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppresses interferon signaling, chemokine production, and antigen presentation in {beta} cells, while reducing activation and cytotoxicity pathways in immune cells. In co-culture studies in vitro, E2 pretreatment of mouse islets reduces subsequent activation of T cells, and in an aggressive adoptive transfer model in vivo, E2 pretreatment of the recipient mice was found to attenuate hyperglycemia. These findings support a model in which E2-mediated {beta}-cell reprogramming reduces {beta}-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.

cell biology↗

bioRxiv2025

The G Protein-Coupled Receptor GPR31 Promotes Pro-inflammatory Responses in Pancreatic Islets and Macrophages

In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting pancreatic {beta} cells. During this process, {beta} cells activate inflammatory signaling pathways that augment the dysfunction and destruction imposed by cellular autoimmunity. The 12-lipoxygenase (12-LOX) pathway produces the pro-inflammatory eicosanoid 12-HETE, which induces oxidative and endoplasmic reticulum stress and results in diminished insulin secretion and apoptosis. The G protein-coupled receptor GPR31 has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout (KO) mice on the C57BL/6J background. To interrogate the role of GPR31 in {beta} cells, we treated islets from wildtype and Gpr31b KO mice with pro-inflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed pathways in Gpr31b KO islets included those pertaining to inflammation and oxidative stress, consistent with functional studies that demonstrated reduced cytokine-induced oxidative stress in Gpr31b KO islets compared to wildtype controls. Bone marrow-derived macrophages from Gpr31b KO mice showed reduced macrophage migration and decreased inflammatory IFN- and IFN-{gamma} signaling by RNA sequencing. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b KO mice were treated with the diabetogenic toxin streptozotocin. Compared to wildtype, Gpr31b KO mice had improved glucose tolerance and preserved {beta}-cell mass. siRNA knockdown of Gpr31b in non-obese diabetic (NOD) mice reduced insulitis, macrophage infiltration, and oxidative stress. Collectively, these findings are consistent with previously published data using 12/15-LOX KO mice and suggest that GPR31 mediates the pro-inflammatory responses of 12-HETE in both {beta} cells and macrophages.

molecular biology↗

bioRxiv2025

12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered these mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased {beta} cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased {beta} cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.

physiology↗

bioRxiv2024

The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin producing pancreatic {beta}-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We found a reduction in the number of proinflammatory macrophages as well as a reduction in iNOS mRNA and protein levels with ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and decreased macrophages to the site of injury after tailfin cut in zebrafish in vivo. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. Our study provides new insights into ISR signaling in macrophages and demonstrates that the ISR might serve as a potential target for intervention in macrophages during early T1D pathogenesis.

immunology↗

bioRxiv2024

Hypusinated and unhypusinated isoforms of eIF5A exert distinct effects in models of pancreas development and function

Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5AHyp) in cellular proliferation is well-characterized, the role of its unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent effects on cellular replication and metabolism distinct from the loss of eIF5AHyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and {beta}-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by the dysregulation of mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely due to the lack of eIF5AHyp. In mice, {beta} cell-specific deletion of DHPS impaired {beta} cell mass expansion and glucose tolerance, while eIF5A deletion had no statistically significant effects. These findings reveal an independent role for eIF5ALys in regulating developmental and functional responses and that a balance in levels of the hypusinated and unhypusinated isoforms of eIF5A may be pivotal in cellular phenotypes in health and disease.

cell biology↗

bioRxiv2024

12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing {beta} cells and involves an interplay between {beta} cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in {beta} cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

molecular biology↗

bioRxiv2023

Suppression of the Integrated Stress Response in Islet β Cells Decreases Risk of Autoimmune Diabetes

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing {beta} cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2 kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves {beta} cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in {beta} cells. Spatial proteomics of islets from these mice shows an increase in the immune checkpoint protein PD-L1 in {beta} cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-{beta}H1 human {beta} cells, interacts with and stabilizes PD-L1. Collectively, our studies show that PERK activity enhances {beta} cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

cell biology↗

bioRxiv2021

12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The inflammatory signals and antigen presentation by these cells may be inducers of the adaptive immune response that is the hallmark of T1D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids from membrane-derived phospholipids, but its role and mechanisms in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of T1D-like islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of {beta}-cells and the subsequent development of hyperglycemia. Depletion or inhibition of 12-LOX in this model resulted in significantly reduced macrophage infiltration into islets with preservation of {beta}-cell mass. In mice, we deleted the gene encoding 12-LOX (Alox15) in the myeloid lineage in the non-obese diabetic (NOD) model of T1D. Myeloid cell-specific Alox15 knockout NOD mice demonstrated reduced insulitis and T-cell responses, preserved {beta} cell mass, and almost complete protection from the development of T1D. A critical effect of 12-LOX depletion appeared secondary to a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration appeared to be secondary to the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migrator defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune myeloid cells in the early pathogenesis of T1D and identify 12-LOX as a necessary enzyme to promote their pro-diabetogenic phenotype in the context of autoimmunity.

immunology↗

bioRxiv2019

Longitudinal Intravital Imaging of Biosensor-labeled In Situ Islet Beta Cells

Impaired function and apoptosis of insulin-secreting islet {beta}-cells is central to disease progression in both type 1 and type 2 diabetes. Oxidative damage resulting from excess reactive oxygen species (ROS) is a central factor in {beta}-cell dysfunction and death, but the dynamic nature of ROS accumulation and its depletion pose a problem for mechanistic studies in vivo. Biosensors, including the redox-sensitive GFP (roGFPs), coupled with intravital microscopy provide a sensitive and dynamic solution to this problem. Here, we utilize a virally-delivered roGFP2-containing human glutaredoxin-1 (Grx1-roGFP2) to selectively monitor {beta}-cell ROS dynamics in vivo in response to toxic glucose analogs. We paired viral biosensor delivery with implanted abdominal imaging windows over the pancreas, thus allowing longitudinal measurements of {beta}-cell ROS and islet area during and after streptozotocin (STZ) exposure. The studies presented here represent a robust experimental platform that could be readily adapted to various transgenic or physiological mouse models in conjunction with any number of available biosensors, and thus opens a vast realm of potential for discovery in islet biology in vivo.

cell biology↗