Biology subjects

Dimonte, S.

Publications and source records attributed to Dimonte, S..

6 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↗

bioRxiv2026

Comprehensive lipidomics of tissue macrophages reveal LTE4-driven eosinophil survival

Tissue-resident peritoneal macrophages (pM[FE]) programmed by GATA6 are essential players regulating immunity and tissue balance in the peritoneal cavity. How GATA6 regulates global lipid metabolism is currently unknown. Addressing this, in myeloid-restricted Gata6-deficient (Gata6-KOmye) mice, significant changes to the pM[FE] lipidome were found. First, Bodipy staining and anti-Stokes Raman scattering (CARS) microscopy demonstrated significant intracellular lipid accumulation in lipid droplets in Gata6-KOmye. Untargeted and targeted lipidomics revealed this to result from increased levels of multiple sphingolipid (SL) molecular species, including sphingomyelins, ceramides, and glycosphingolipids, along with upregulation of the cysteinyl leukotriene (CysLTs) pathway at both lipidomic and transcriptional levels. Evidencing a functional role for the lipidomic phenotype, Gata6-KOmye showed significant eosinophil accumulation, associated with decreased apoptosis which was exclusively driven by CysLT signalling. In summary, GATA6 is demonstrated as a regulator of sphingolipid accumulation and CysLT generation in pM[FE], with secondary impacts on associated leukocytes through regulation of transcellular CysLT signaling.

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↗

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↗

bioRxiv2021

IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

Interferon induced transmembrane protein 3 (IFITM3) is an important viral restriction factor in viral pathogenesis that also exhibits poorly understood immune regulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 regulates MyD88-dependent TLR-mediated cytokine production following dendritic cell exposure to cytomegalovirus (CMV), and this process limits viral pathogenesis in vivo. IFITM3 also restricted pro-inflammatory (IL-6) cytokine production in response to influenza. IFITM3 bound to and promoted ubiquitination and proteasomal degradation of the reticulon 4 isoform Nogo-B. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and this process involved alteration of TLR dynamics. The anti-inflammatory function of IFITM3 was intrinsically linked to its ability to regulate Nogo-B. Thus, we uncover Nogo-B as an unappreciated driver of viral pathogenesis and highlight a novel immune regulatory pathway where IFITM3 fine-tunes TLR responsiveness of myeloid cells to viral stimulation.

immunology↗

bioRxiv2020

Optimal CD8+ T-cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Cytomegalovirus (CMV) induction of large frequencies of highly functional memory T-cells has attracted much interest in the utility of CMV-based vaccine vectors, with exciting preclinical data obtained in models of infectious diseases and cancer. However, pathogenesis of human CMV (HCMV) remains a concern. Attenuated CMV-based vectors, such as replication- or spread-deficient viruses potentially offer an alternative to fully replicating vectors. However, it is not well-understood how CMV attenuation impacts vector immunogenicity, in particularly when administered via relevant routes of immunization such as the skin. Herein we used the murine cytomegalovirus (MCMV) model to investigate the impact of vector attenuation on T-cell memory formation following subcutaneous administration. We found that the spread deficient virus ({Delta}gL-MCMV) was impaired in its ability to induce memory CD8+ T-cells reactive to some (M38, IE1) but not all (IE3) viral antigens. Impaired memory T-cell development was associated with a preferential and pronounced loss of polyfunctional (IFN-{gamma}+ TNF-+) T-cells, and was not rescued by increasing the dose of replication-defective MCMV. Finally, whilst vector attenuation reduced dendritic cell (DC) recruitment to skindraining lymph nodes, systematic depletion of multiple DC subsets during acute subcutaneous MCMV infection had a negligible impact on T-cell memory formation, implying that attenuated responses induced by replication-deficient vectors were likely not a consequence of impaired initial DC activation. Thus, overall, these data imply that the choice of antigen and/or cloning strategy of exogenous antigen in combination with the route of immunization may influence the ability of attenuated CMV vectors to induce robust functional T-cell memory.

immunology↗