Biology subjects

Arribas, S. M.

Publications and source records attributed to Arribas, S. M..

3 recordsLinked to original sources

bioRxiv2026

Lamin A/C regulates the compartment-specific contributions of immune and stromal cells to intestinal inflammation and colitis-associated colon cancer

Inflammatory bowel disease (IBD) arises from dysregulated crosstalk between innate immune, adaptive immune, and stromal compartments, yet the compartment-specific mechanisms driving tissue injury and tumorigenesis remain incompletely defined. To address this gap, we used conditional knockout and overexpression mouse models together with human IBD biopsy analysis to dissect the compartment-specific roles of lamin A/C in intestinal inflammation and colitis-associated tumorigenesis. Pan-hematopoietic lamin A/C deletion attenuated acute dextran sulfate sodium (DSS)-induced colitis. Myeloid-specific lamin A/C deletion ameliorated chronic colitis and was associated with altered dendritic cell (DC) programs, enhanced regulatory T cell (Treg) responses, and reduced effector T cell activation. Adoptive transfer of lamin A/C-deficient bone marrow-derived DCs recapitulated this reduced-damage phenotype in DSS colitis, while proteomic profiling revealed reduced antigen-processing and inflammatory programs together with enhanced metabolic and mucosal defense pathways. T cell-specific lamin A/C deletion reduced the Th1/Treg ratio and limited tumor development by suppressing chronic inflammation, whereas T cell-specific lamin A/C overexpression promoted severe Th1-skewed pathology, sustained intestinal inflammation, and increased colitis-associated tumor burden. Stromal fibroblast-specific lamin A/C deletion generated a tissue-protective niche characterized by enhanced epithelial barrier gene expression, regulatory cytokine production, and remodeling of the local immune milieu. Human IBD biopsies revealed compartment-specific lamin A/C alterations consistent with the murine findings. In lamina propria CD3 T cells, lamin A/C levels were blunted in IBD and associated with local histological severity rather than IBD diagnosis, whereas epithelial lamin A/C showed a steeper crypt-axis spatial gradient in a Crohns disease-specific pattern. Together, these findings identify lamin A/C as a cell-type- and context-dependent regulator of intestinal inflammation and tumorigenesis.

immunology↗

bioRxiv2024

Role of Lamin A/C on dendritic cell function in antiviral immunity

Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFN{gamma}-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFN{gamma}-producing -CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primary Vaccinia virus (VACV) infection. Remarkably, in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naive CD4 T cells. Lamin A/C deletion induces alterations in NF{kappa}B nuclear localization, thereby influencing NF{kappa}B-dependent transcription. Furthermore, lamin A/C ablation modifies the epigenetic signature of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and elucidates the molecular mechanisms through which lamin A/C modulates DC function via epigenetic and transcriptional regulation.

immunology↗

bioRxiv2024

Segmental regulation of intestinal motility by colitis and the adaptive immune system in the ileum and colon

Gastrointestinal motility disturbances are common in inflammatory bowel disease (IBD); however, their exact causes remain elusive. This study explores the motility of various intestinal segments in both healthy and IBD states, focusing on the role of the adaptive immune system. Using a dextran sulfate sodium (DSS)-induced colitis model in mice lacking B and T lymphocytes, we evaluated motility in the ileum and colon using an organ bath system. In healthy mice, absence of adaptive lymphocytes in the ileum reduces muscarinic receptor sensitivity or increase cholinesterase activity. Colitis increases motility, intensifying the intensity and frequency of spontaneous contractions while decreasing responsiveness to cholinergic stimuli. In the proximal colon, healthy mice lacking adaptive immune system exhibit increased contractile capacity and frequency, along with reduced muscarinic receptor sensitivity or increased cholinesterase activity. Conversely, colitis diminishes contractile capacity regardless of genotype, while recovery increases frequency of spontaneous contractions. In the mid-colon during colitis, healthy mice lacking adaptive immune system exhibit reduced muscarinic receptor sensitivity or increased cholinesterase activity, while the absence of adaptive lymphocytes during colitis exacerbates both spontaneous and stimuli-induced contractions. Finally, in the distal colon, the adaptive immune system enhances stimuli-induced contractility in health and reduces contractility and enhances muscarinic responses during colitis. Overall, intestinal motility in both the ileum and colon is finely regulated, with the adaptive immune system playing a crucial role. These findings contribute to our understanding of IBD pathology, emphasizing the importance of investigating gastrointestinal motility in IBD research.

immunology↗