Biology subjects

Jones, G. W.

Publications and source records attributed to Jones, G. W..

9 recordsLinked to original sources

bioRxiv2026

Inflammatory arthritis disrupts ocular immune privilege by compromising blood-retinal barrier integrity and promoting uveitogenic T cell recruitment

Inflammatory arthritis and uveitis frequently co-exist, yet the mechanisms linking joint and ocular inflammation remain ill-defined. Here, we investigated how inflammatory arthritis influences ocular immune homeostasis using murine models of antigen-induced arthritis and collagen-induced arthritis. Arthritis promoted the accumulation of T cells, myeloid cells, and neutrophils within the vitreoretinal compartment, without progression to overt clinical uveitis. Ocular leukocyte recruitment was dynamically coupled to arthritis activity, resolving with remission of joint inflammation and recurring during arthritic flares. The magnitude of ocular immune perturbation correlated with arthritis severity, being enhanced in IL-27R-deficient mice and markedly reduced in IL-6R-deficient mice. Mechanistically, arthritis increased blood-retinal barrier permeability, demonstrating that systemic inflammation perturbs ocular immune privilege even in the absence of apparent ocular disease. While arthritis alone was insufficient to induce uveitis, it established a permissive ocular microenvironment that selectively enhanced the recruitment of adoptively transferred uveitogenic CD4+ T cells. These findings identify inflammatory arthritis as a systemic driver of subclinical ocular immune dysregulation and reveal a mechanism by which inflammation at a distant site may promote vulnerability to ocular autoimmunity. These data provide a framework for understanding immune dysregulation at the joint-eye axis and highlight cytokine pathways that may be targeted to preserve ocular immune homeostasis.

immunology↗

bioRxiv2025

Discrete cytokine signaling networks instruct distinctsynovial pathotypes in inflammatory arthritis

Patients with rheumatoid arthritis (RA) display distinct patterns of synovitis. To define the inflammatory mechanisms driving this heterogeneity, we analyzed the inflamed synovium of wild-type (WT), Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis (AIA). Remarkably, each strain developed a joint pathology mirroring a major RA synovial pathotype: myeloid-rich (WT), fibroblast-rich/pauci-immune (Il6ra-/-), and lymphoid-rich (Il27ra-/-) synovitis. Histology confirmed minimal immune infiltration in Il6ra-/- joints, while WT and Il27ra-/- mice exhibited prominent immune involvement, including organized synovial lymphoid-like aggregates in Il27ra-/- mice. Transcriptomic and epigenomic profiling revealed both shared and distinct regulatory programs among genotypes. Il6ra-/- mice showed increased WNT, DKK, and AMPK signaling associated with fibroblast, chondrocyte, and osteoclast activation (e.g., Adamts19, Dkk1, Ecm1). Consistent with synovial ectopic lymphoid-like structures, Il27ra-/- mice showed enrichment of lymphocyte activation (e.g., Il17a, Il22, Bhlhe40). WT mice exhibited hallmarks of MAP kinase activation. These molecular signatures parallel those of fibroblast-, lymphoid-, and myeloid-rich synovitis in RA. Defining a STAT1-STAT3 regulatory interplay influencing transcriptional decisions in WT and Il27ra-/- mice, our findings offer insights into cytokine-driven disease heterogeneity. Together, these results establish a framework for mechanism-based classification of synovitis and introduce new mouse models to study the molecular drivers of synovial pathotypes and treatment response.

pathology↗

bioRxiv2025

Travelling Waves in Gene Expression: A Mathematical Model of Cell-State Dynamics in Melanoma

Melanoma is a cancer of the melanocyte, known to have an ability to readily switch between different transcriptional cell states that convey different phenotypic properties (e.g. hyper-differentiated, neural crest-like). This ability is believed to underpin intratumour heterogeneity and plastic adaptation, which contributes to resistance to therapy and immune evasion of the tumour. Therefore, understanding the mechanisms underlying acquisition of transcriptional cell states and cell-state switching is crucial for the development of therapies. We model a minimal gene regulatory network comprising three key transcription factors, whose varying gene expression encodes different melanoma cell states, and use deterministic spatiotemporal differential-equation models to study gene-expression dynamics. We exploit an approximation, based on cooperative binding of transcription factors, in which the models are piecewise-linear. We classify stable states of the local model in a biologically relevant manner and, using a naive model of intercellular communication, we explore how a population of cells can take on a shared characteristic through travelling waves of gene expression. We derive a condition determining which characteristic will become dominant, under sufficiently strong cell-cell signalling, which creates a partition of parameter space.

cancer biology↗

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↗

bioRxiv2025

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. /{beta}-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of -ketoglutarate dehydrogenase (-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643996v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@bb3fcborg.highwire.dtl.DTLVardef@1594fc8org.highwire.dtl.DTLVardef@84e078org.highwire.dtl.DTLVardef@1ad023e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Morphodynamics of tip growing cells

Pollen tubes, root hairs and fungal hyphae elongate by adding material at their tips. The region in the immediate vicinity of the tip is dynamically pliable and allows for the addition of new wall material even as it flows in response to the turgor that drives it. Any imbalance between the rate of material addition and its consequent flow will cause a tip growing cell to either burst because its wall thins or stop growing because its wall thickens. We use an experimentally-inspired feedback law that couples vesicle exocytosis to wall mechanics via the local strain rate to construct a minimal theory for the dynamics of tip growing cells. Our theory characterizes the parameter regime where stable steady tip growth is possible in terms of two dimensionless parameters: a scaled turgor pressure, and a ratio of length scales describing gradients of wall extensibility and vesicle composition near the tip. Our analysis also explains the experimentally observed shape response of tip growing cells observed when external turgor is dynamically varied. All together our formalism provides a general framework for the coupled dynamics of internal vesicular transport and wall mechanics in tip-growing cells.

plant biology↗

bioRxiv2024

IL-6 and IL-27 negatively regulate CRTAM-expressing CD4+ T-cells associated with lymphoid-driven synovitis.

ABSTRACT-Joint pathology in rheumatoid arthritis is heterogeneous, with histology providing evidence of fibroblast-driven, myeloid-driven, and lymphoid-driven synovitis. However, the immuno-modulatory pathways underlying their development remain unclear. Profiling synovial tissues from rheumatoid arthritis patients and mice with antigen-induced arthritis, we identified a subset of synovial infiltrating CD4+ T-cells expressing CRTAM (class-I MHC-restricted T-cell-associated molecule). In human synovial biopsies, CRTAM correlated with the expression of effector cytokines (IL21, IFNG), chemokine receptors (CXCR3, CXCR4, CCR5), granzymes (GZMA, GZMB, GZMK), and regulatory factors (TIGIT, EOMES, BATF) linked with T-cell-mediated immunity. Studies of antigen-induced arthritis showed that CRTAM+CD4+ T-cells accumulate in the inflamed synovium following disease onset. CRTAM+CD4+ T-cells were particularly abundant in synovial tissue from Il27ra-/- mice displaying ectopic lymphoid-like structures. CADM1 (cell adhesion molecule-1), the endogenous ligand for CRTAM, was also expressed in human synovitis and synovial tissues from wild-type, Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19+ cells. Considering the ex vivo regulation of CRTAM, we identified that activation of naive CD4+ T-cell increased CRTAM expression. This induction was blocked by IL-6 and IL-27, with further studies identifying a role for STAT3 in controlling the CRTAM transcriptional repressor, ZEB1. These results provide insights into the cytokine control of CRTAM on CD4+ T-cells and support the involvement of CRTAM+CD4+ T-cells in lymphoid-driven synovitis.

immunology↗

bioRxiv2023

IL-27 maintains cytotoxic Ly6C+ gamma delta T cells that arise from immature precursors

In mice, {gamma}{delta} T cells that express the co-stimulatory molecule, CD27, are committed to the IFN{gamma}-producing lineage in the thymus, and in the periphery, these cells play a critical role in host defence and anti-tumor immunity. Unlike {beta} T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted {gamma}{delta} T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFN{gamma}-producing {gamma}{delta} T cells. We found that immature CD27+Ly6C-- cells convert into mature CD27+Ly6C+ cells, and these mature cells control cancer progression while the immature cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature {gamma}{delta} T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human V{delta}2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C-- cells and human V{delta}1+ cells. These data reveal increased complexity within IFN{gamma}-producing {gamma}{delta} T cells, comprising of immature and terminally differentiated subsets, that offer new insights into unconventional T cell biology.

immunology↗

bioRxiv2022

Effector Th1 cells alter the transcriptional output of IL-6 in acute resolving inflammation

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, anti-microbial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA-seq, ChIP-seq, and ATAC-seq to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focussed on the transcriptional signature of the immuno-modulatory cytokine IL-6 in both settings and examined how pro-fibrotic IFN{gamma}-secreting CD4+ T-cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting anti-microbial immunity and tissue homeostasis. The introduction of IFN{gamma}-secreting CD4+ T-cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent GAS motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T-cells re-tune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

immunology↗