Biology subjects

Fearon, U.

Publications and source records attributed to Fearon, U..

3 recordsLinked to original sources

bioRxiv2025

Disease-specific fibroblast-myeloid interactions in rheumatoid arthritis synovium

Rheumatoid arthritis (RA) is characterized by profound remodeling of the synovial microenvironment. Here we show that enhanced fibroblast-macrophage cross-talk distinguishes RA from psoriatic arthritis (PsA). MerTK-SPP1 macrophages represent the dominant inflammatory myeloid population in RA, interacting with expanded fibroblast subsets through SPP1-mediated signaling. Lining fibroblasts display induction of antigen-presentation and IL-6/JAK-STAT pathways, while a CHI3L1-producing fibroblast population arises specifically in RA and may act as a source of autoantigens. These stromal populations interact closely with FABP5 iDC3 cells and T cells within a disrupted synovial lining, creating a niche driving adaptive immune activation. In contrast, PsA exhibits increased fibroblast- endothelial interactions without major endothelial transcriptional changes. Our data identify SPP1 signaling and fibroblast-myeloid-dendritic interactions as core drivers of RA synovial inflammation that links innate immune activation to the initiation of autoimmunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/688477v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@c76e39org.highwire.dtl.DTLVardef@11563a9org.highwire.dtl.DTLVardef@141f3fborg.highwire.dtl.DTLVardef@f90742_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Distinct myeloid precursors and their interaction with mesenchymal cells orchestrate the spreading of psoriatic disease from the skin to the joints

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/665302v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@38c440org.highwire.dtl.DTLVardef@dc574dorg.highwire.dtl.DTLVardef@1e79f72org.highwire.dtl.DTLVardef@19508cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

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↗