Biology subjects

Gonzalez-Granado, J. M.

Publications and source records attributed to Gonzalez-Granado, J. M..

5 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↗

bioRxiv2026

The transcription factor NF-Y promotes myeloid cell survival and protects from inflammatory vascular disease

BackgroundMyeloid cells orchestrate vascular inflammation through transcriptional programs that regulate their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, understanding of the transcriptional regulation of myeloid behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation. Here, we investigate the role of NF-Y in myeloid function and survival during chronic vascular inflammation. MethodsIntegrated single-cell transcriptomics of BM, blood, and atherosclerotic lesions were combined with myeloid-specific NF-YA inactivation to define NF-Y-dependent transcriptional states. Functional consequences were assessed in mice with myeloid-specific Nfya deletion on a hypercholesterolemic Apoe-/- background using models of diet-induced advanced atherosclerosis and endoluminal femoral injury. Myeloid cell recruitment, survival, apoptosis, and proliferation were further examined in models of thioglycolate-induced peritonitis. ResultsNF-Y subunit transcripts were detected across myeloid compartments, with Nfya enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low Nfya expression was associated with lipid-handling and phagocytic macrophage signatures and a pro-inflammatory neutrophil phenotype. Myeloid Nfya deficiency was further associated with reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, larger unstable atherosclerotic lesions, and aggravated atherosclerosis and injury-induced neointimal thickening. ConclusionOur data identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.

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↗

bioRxiv2022

Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages

Aging is characterized by gradual immune dysfunction and increased risk for many diseases, including respiratory infections. Genomic instability is thought to play a central role in the aging process but the mechanisms that damage nuclear DNA in aging are insufficiently defined. Cells that migrate or reside within confined environments experience forces applied to their nucleus, leading to transient nuclear envelope (NE) ruptures. NE ruptures are associated with DNA damage, and Lamin A/C is required to limit these events. Here, we show that Lamin A/C protects lung alveolar macrophages from NE rupture and hallmarks of aging. Lamin A/C ablation in immune cells results in a selective depletion of lung alveolar macrophages (AM) and a heightened susceptibility to influenza infection. Lamin A/C-deficient AM that persist display constitutive nuclear envelope rupture marks, DNA damage and p53-dependent senescence. In wild-type mice, we found that AM migrate within constricted spaces in vivo, at heights that induce NE rupture and DNA damage. AM from aged wild-type mice and from Lamin A/C-deficient mice share an upregulated lysosomal signature with CD63 expression, and we find that CD63 is required to clear damaged DNA in macrophages. We propose that induction of genomic instability by NE disruption represents a mechanism of aging in alveolar macrophages.

immunology↗