Biology subjects

Gonzalo, P.

Publications and source records attributed to Gonzalo, P..

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↗

bioRxiv2021

The Endoplasmic Reticulum pool of Bcl-xL dampens the Unfolded Protein Response through IP3R-dependent Calcium Release

Apoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localization and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localization is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we showed that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs demonstrated a reduced expression of the Unfolded Protein Response (UPR) markers upon ER stress and displayed reduced inositol trisphosphate receptor (IP3R)-mediated ER calcium release. Collectively, our data show that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the ER, apart from its cliche regulation of apoptosis.

cell biology↗

bioRxiv2020

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ after myocardial infarction

Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP{Delta}LysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGF{beta}1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP{Delta}LysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

immunology↗

bioRxiv2020

Isoprenylcysteine carboxylmethyltransferase basedtherapy for Hutchinson Gilford progeria syndrome

Progerin is a mutant prelamin A variant that causes Hutchinson-Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria.

pharmacology and toxicology↗