Biology subjects

Jenkins, V.

Publications and source records attributed to Jenkins, V..

2 recordsLinked to original sources

bioRxiv2025

Interleukin-6 elevates thrombosis via pro-coagulant phospholipids from platelet 12-lipoxygenase in rheumatoid arthritis.

BackgroundRheumatoid arthritis (RA) is associated with significantly higher thrombotic risk, which is not yet mechanistically understood. Here, the role of pro-coagulant membranes of platelets and blood cells in driving thrombosis, and their regulation by inflammation was determined using human cohorts and genetically-modified mice. MethodsAntigen-induced arthritis (AIA) was induced in WT, Il27ra-/-, Il6ra-/-, Alox12-/- and Alox15-/- mice. Coagulation and inflammatory markers were measured in plasma. Lipidomics was performed on blood cells and synovium analyzing pro-coagulant enzymatically-oxidized phospholipids (eoxPL) and oxylipins. Two human RA patient cohorts were characterized for eoxPL generation in blood cells, and chronic immune response to eoxPL in vivo. ResultsAIA induction significantly elevated plasma thrombin-antithrombin (TAT) complexes, serum amyloid A (SAA), and eoxPL in blood cells and platelets. Elevations in TATs, SAA and eoxPL were suppressed by genetic deletion of IL-6Ra, while platelet Alox12 deletion prevented TAT and eoxPL increases. This indicates a direct role for IL-6 in elevating thrombosis via upregulation of platelet eoxPL. In contrast, leukocyte Alox15 deletion did not impact TATs or eoxPL. Deletion of either LOX isoform worsened AIA joint pathology. Synovial tissue demonstrated raised eoxPL, but exclusively from Alox15, indicating leukocyte origin. Thus, both LOX isoforms contribute to AIA, but through different mechanisms. In human RA, platelet counts, and plasma TATs were elevated, and plasma had significantly elevated IgG against eoxPL, indicating patients experience chronic exposure to the lipids in vivo. ConclusionsPlatelet-derived pro-coagulant eoxPL are elevated in human and murine arthritis along with higher coagulation markers. In mice, this was mediated by the IL-6/Alox12 axis and directly responsible for the higher thrombotic risk. IL-6 plays a central role in driving platelet activation in RA, with the pro-coagulant lipid membrane representing a novel target. Reducing inflammation using DMARDs, particularly targeting IL-6 may reduce platelet pro-coagulant activity and thrombosis risk in RA.

pharmacology and toxicology↗

bioRxiv2024

Multi-modal comparison of molecular programs driving nurse cell death and clearance in Drosophila melanogaster oogenesis

The death and clearance of nurse cells is a consequential milestone in Drosophila melanogaster oogenesis. In preparation for oviposition, the germline-derived nurse cells bequeath to the developing oocyte all their cytoplasmic contents and undergo programmed cell death. The death of the nurse cells is controlled non-autonomously and is precipitated by epithelial follicle cells of somatic origin acquiring a squamous morphology and acidifying the nurse cells externally. Alternatively, stressors such as starvation can induce the death of nurse cells earlier in mid-oogenesis, manifesting apoptosis signatures, followed by their engulfment by epithelial follicle cells. To identify and contrast the molecular pathways underlying these morphologically and genetically distinct cell death paradigms, both mediated by follicle cells, we compared their genome-wide transcriptional, translational, and secretion profiles before and after differentiating to acquire a phagocytic capability, as well as during well-fed and nutrient-deprived conditions. By coupling the GAL4-UAS system to Translating Ribosome Affinity Purification (TRAP-seq) and proximity labeling (HRP-KDEL) followed by Liquid Chromatography tandem mass-spectrometry, we performed high-throughput screens to identify pathways selectively activated or repressed by follicle cells to employ nurse cell-clearance routines contextually and preferentially. We also integrated two publicly available single-cell RNAseq atlases of the Drosophila ovary to define the transcriptomic profiles of follicle cells. In this report, we describe the genes and major pathways identified in the screens and the striking consequences to Drosophila melanogaster oogenesis caused by RNAi perturbation of prioritized candidates. To the best of our knowledge, our study is the first of its kind to comprehensively characterize two distinct apoptotic and non-apoptotic cell death paradigms in the same multi-cellular system. Beyond molecular differences in cell death, our investigation may also provide insights into how key systemic trade-offs are made between survival and reproduction when faced with physiological stress.

genetics↗