Biology subjects

Polari, L.

Publications and source records attributed to Polari, L..

6 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

Keratin 7 protein presence in stool is indicative of active pediatric-onset inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) is associated with early structural changes in intestinal epithelial cells; however, the associated molecular alterations remain incompletely understood. The cytoskeletal protein keratin (K) 7 was recently found to be focally expressed in the colonic epithelium in IBD, while absent in the healthy colon. Here, we investigated the applicability of K7 as a noninvasive stool biomarker for pediatric IBD. MethodsIn this case-control study including adolescent patients with IBD (n=27) and healthy controls (n=15), stool lysates were analyzed by proteomics, immunoassay and qPCR to determine K7 protein and mRNA content, respectively. Additionally, stool mRNA levels of the simple epithelial keratins, K8, K18, K19 and K20, were measured. ResultsStool proteomic analysis identified focal K7 and K19 in IBD samples. Additionally, 23 differentially abundant proteins, of which 18 were higher in IBD, were identified and Gene Ontology enrichment analysis highlighted immune and inflammatory pathways. K7 specific immunoassay detected fecal K7 protein in all patients with active IBD, including both ulcerative colitis and Crohns disease, while K7 was near or below the detection limit in controls and IBD patients in remission (area under ROC curve=0.88, p<0.0001). While KRT7 mRNA levels were below the detection limit, KRT8 and KRT18 transcripts were elevated in IBD samples compared to controls (p<0.05). ConclusionsK7 protein is elevated in IBD patient stool, reflecting intestinal de novo expression and increased epithelial cell exfoliation. Fecal K7 may provide a novel, noninvasive marker for IBD diagnosis and monitoring.

cell biology↗

bioRxiv2026

The expression of colonic keratins is elevated in IBD, reduced in microscopic colitis, and unchanged in IBS : a retrospective study

BackgroundKeratins, a major subgroup of intermediate filament proteins, play a critical role in maintaining epithelial barrier and intracellular epithelial integrity. Studies have demonstrated possible links between inflammatory signaling and colonic keratins type II K8, and type I K18, K19 and K20, in animal models of colitis, and in patients with Inflammatory Bowel Disease (IBD). K7 is de novo expressed in patients with the IBD subtypes Ulcerative Colitis (UC) and Crohns Disease (CD). However, the histopathological roles of colonocyte keratins across IBD, microscopic colitis (MC), and Irritable Bowel Syndrome (IBS) remain poorly understood. Given the established utility as biomarkers in cancer diagnostics, we investigated whether keratin expression patterns could be used to distinguish inflammatory and functional colonic disorders. MethodsBiobank samples from patients with IBD (n=27), MC (n=18), IBS (n=32) and healthy controls (n=31), were collected and immunohistochemically stained for K7, K8, K18, K19, and K20. Digital image analysis quantified staining intensities, which were correlated with histopathological severity scores and clinical parameters. ResultsColonic keratin expression was significantly elevated in IBD, particularly in UC, while they were decreased in MC, and unaltered in IBS. Notably, K8 and K19 expression were strongly associated with areas of severe epithelial damage in IBD. Keratin expression was most pronounced in patients who had undergone colectomy due to treatment-resistant IBD. DiscussionKeratin changes in IBD and MC but not in IBS highlight their importance in maintaining barrier homeostasis. Whether these changes are causes or consequences for these diseases will warrant further research.

cell biology↗

bioRxiv2025

Genetically induced mouse model for colon-specific epithelial cell tumorigenesis driven by loss of K8 and Apc

Loss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyperproliferation and tumorigenesis. However, most colorectal cancer (CRC) mouse models require carcinogen, develop small intestinal tumors or have long latency period. The aim was to establish a genetic, colon-specific and more human like CRC model driven by loss of K8 and Apc. Colon epithelium specific targeting using the CDX2P-CreERT2 mice was used to generate K8flox/flox; CDX2P-CreERT2 and K8flox/flox; CDX2P-CreERT2; Apcflox/+ mice. Body weight and stool consistency were monitored, and colon was analyzed for tumor burden and histopathology. Keratin expression, inflammation, and proliferation were assessed using immunoblotting and immunofluorescence analysis. This data was compared to K8 expression analysis in patients with CRC using UALCAN database. K8 downregulation in adult K8flox/flox; CDX2P-CreERT2 mice triggers mild diarrhea and leads to loss of K8 and reduced partner keratin levels in a mosaic pattern in the colonic epithelium, while ileal K8 protein levels are unchanged. K8-negative colon areas display increased crypt loss and more MPO+ cells predominantly in the proximal colon. Increased colonocyte proliferation is observed as increased percentage of Ki67+ cells and lower IL-22BP protein levels throughout the colon. These mice with additional monoallelic Apc inactivation show increased colon tumor formation. In colon adenocarcinoma patients, K8 expression is decreased independent of disease type and stage, age or gender. New genetic and colon-specific mouse model with loss of K8 and Apc adequately resembles human CRC. This study also highlights a role of colonocyte K8 in maintaining colon epithelial integrity and protecting against colon tumorigenesis.

cancer biology↗

bioRxiv2025

Exacerbated salmonellosis in poly(ADP-ribose) polymerase 14 deficient mice

Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) is an enteropathogen annually causing millions of acute infections ranging from gastroenteritis to life-threatening invasive systemic disease. Strong mucosal inflammation is characteristic for the infection driven by the innate immune receptor activation but also directly by the invading bacterium. It remains unknown how and at which point the mucosal inflammation turns anti-bacterial and how the tissue homeostasis is restored. Here, we investigated the expression and function of poly(ADP-ribose)polymerase (Parp14), a known cytoplasmic and nuclear regulatory protein of immune cells, in the mouse streptomycin-pretreatment model of S. Typhimurium infection. In the infected mice, Parp14 expressing cells, some of which were macrophages, were detected throughout the gastrointestinal tract. However, the most strongly Parp14 expressing cells were the epithelial cells. Based on small intestine single cell RNA-Seq analysis of different epithelial cell types, the expression of parp14 was pronounced in the enterocytes and Tuft cells. Mice with a body-wide genetic deficiency of Parp14 suffered from exacerbated S. Typhimurium colitis. The histopathological analysis of the large intestine revealed increased immune cell infiltration, Goblet cell loss, and epithelial erosion. At the same time lower numbers of viable bacteria were detected. Based on a bulk tissue RNA-Seq analysis, transcriptional signatures either missing or down-regulated in the infected Parp14 deficient mice were detected. These signatures were enriched with genes related to cell adhesion, cell division and cytoskeletal rearrangements, and genes related to infection and immune responses. It appears that Parp14 has potential functions in the regulation of tissue architecture and mucosal inflammation in the large intestine of S. Typhimurium infected mice.

microbiology↗

bioRxiv2024

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, using a biobank IBD patient cohort as well as two mouse models of colitis, i.e., the IBD-mimicking oral dextran sulfate sodium (DSS) exposure model, and the oral Salmonella exposure model. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both colitis models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis. The Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not affect the mouse colon bacterial microbiota based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice were normal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection responses both prior and after the 1-week DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

immunology↗