Biology subjects

Matteoli, G.

Publications and source records attributed to Matteoli, G..

8 recordsLinked to original sources

bioRxiv2024

Unveiling the guardians: IL-26-expressing MAIT cells protect epithelial barrier function and are dysregulated in Crohn's disease

BACKGROUND & AIMSInflammatory bowel disease (IBD) is characterized by a dysregulated immune response against the hosts microbiome. Mucosal-associated invariant T (MAIT) cells recognize microbiota-derived riboflavin metabolites and play a crucial role in mucosal homeostasis. However, their specific role in IBD remains enigmatic. MAIT cells express IL-26, a novel IL-10 family cytokine with a controversial role in IBD. We investigated the functions of MAIT cells and IL-26 in IBD using a unique combination of state-of-the-art 3D human intestinal tissue models and clinical samples. METHODSWe analyzed MAIT cells from the peripheral blood and intestinal tissue of Crohns disease (CD) patients, using immunofluorescence staining and flow cytometry to describe the phenotype and IL-26 expression of MAIT cells. We used 3D iPSC-derived intestinal organoids as a complex in vitro model of human tissue and RNA sequencing and functional assays such as wound healing assay to study the role of IL-26 in mucosal homeostasis and inflammation. RESULTSWe observed a reduction of MAIT cells in the peripheral blood of CD patients compared to healthy donors (1.5 {+/-} 0.4%; 4.1 {+/-} 1.1%; p < .0065) and a significant decrease of MAIT cells in inflamed compared to non-inflamed ileum of CD patients (0.1 {+/-} 0.03%; 0.17 {+/-} 0.05%; p < .042). MAIT cells were found pathologically activated in inflamed tissue, exhibiting differences in CD8 and CD4 expression and dysregulation of IL-26 expression. Furthermore, we demonstrated a protective role of IL-26 in mucosal homeostasis and inflammation in the iPSC-derived organoid model. CONCLUSIONOur results show a crucial role for IL-26 and MAIT cells in the homeostasis of intestinal tissue and in the pathogenesis of IBD. These cells may therefore represent new therapeutic targets for CD patients.

immunology↗

bioRxiv2023

IL-1R signaling drives enteric glia-macrophage interaction in colorectal cancer progression

Enteric glial cells (EGCs) have been implicated in colorectal cancer (CRC) pathogenesis. However, their precise mechanisms of interaction with the CRC immune cell compartment and pro-tumorigenic role remain unclear. This study aimed to investigate the immunomodulatory effects of EGCs on tumor-associated macrophages (TAMs) and their involvement in CRC progression. Using EGC depletion and supplementation models, we assessed the impact of EGCs on the immunomodulation of orthotopic murine CRC. Furthermore, by making use of Bulk RNA-sequencing of CRC EGCs and single-cell sequencing of the tumor microenvironment, we identified the factors involved in the EGC-TAM crosstalk. Findings demonstrate that EGCs acquire a reactive and immunomodulatory phenotype in both murine CRC models and patients, influencing TAM differentiation. Mechanistically, secretion of IL-1 by tumor-infiltrating monocytes and macrophages triggers the phenotypic and functional switch of CRC EGCs via IL-1R. Consequently, tumor EGCs secrete IL-6, promoting the differentiation of monocytes into pro-tumorigenic SPP1+ TAMs. Importantly, the reactive tumor EGCs phenotype correlates with worse disease outcomes in preclinical models and CRC patients. Here we uncover a previously unexplored neuroimmune interaction between EGCs and TAMs within the colorectal tumor microenvironment, informing potential therapeutic strategies and enhancing our understanding of CRC progression. eTOC SummaryOur study unveils a novel neuroimmune interaction between enteric glia and TAMs in colon carcinoma. Monocyte/Macrophage-derived IL-1 activates enteric glia, leading to the differentiation of pro-tumorigenic SPP1+ TAMs via glial-derived IL-6. Blocking glial IL-1R-signaling reduces colonic tumor lesions, highlighting IL-1R as a potential therapeutic target.

cancer biology↗

bioRxiv2023

Intercellular interaction between FAP fibroblasts and CD150 inflammatory monocytes mediates fibro-stenosis in Crohn's disease

Crohns disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate complex intercellular interactions leading to fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells expressing CD150 induce a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) production. Therapeutic inhibition of TWIST1 inhibits fibroblast activation, reducing ECM production and deposition. These findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

immunology↗

bioRxiv2021

Enteric glial cells favour accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation

ObjectiveMonocyte-derived macrophages (M{varphi}s) are crucial regulators during muscularis inflammation. However, it is unclear which microenvironmental factors are responsible for monocyte recruitment and neurotrophic M{varphi} differentiation in this paradigm. Here, we investigate M{varphi} heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue protective M{varphi}s. DesignSingle cell RNA sequencing was performed on immune cells from the muscularis of wild-type and CCR2-/- mice at different timepoints after muscularis inflammation. CX3CR1GFP/+ and CX3CR1CreERT2 R26YFP mice were analyzed by flow cytometry and immunofluorescence. The transcriptome of enteric glial cells (EGCs) was investigated using PLPCreERT2 Rpl22HA mice. In addition, we assessed the effect of supernatant from neurosphere-derived EGCs on monocyte differentiation based on the expression of pro- and anti-inflammatory factors. ResultsMuscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving M{varphi} subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo M{varphi}s, which were both derived from CCR2+ monocytes. Interestingly, we found that EGCs were able to sense damage to the muscularis to stimulate monocyte recruitment and differentiation towards pro-resolving M{varphi}s via CCL2 and CSF1, respectively. ConclusionOur study provides a comprehensive insight into pro-resolving M{varphi} differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and M{varphi}s, thereby highlighting pro-resolving M{varphi} differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

immunology↗

bioRxiv2020

HIV-1 provirus excised by single CRISPR/Cas9 RNA guide persists in host cell and may be reactivated

Gene editing may be used to cut out the human immunodeficiency virus type-1 (HIV-1) provirus from the host cell genome and eradicate infection. Here, using cells acutely or latently infected by HIV and treated with long terminal repeat-targeting CRISPR/Cas9, we show that the excised HIV provirus persists for a few weeks and, by means of HIV Integrase, rearranges in circular molecules. Circularization and integration restore proviral transcriptional activity that is enhanced in the presence of exogenous Tat and Rev or tumor necrosis factor-, respectively, in acutely or latently infected cells. Although confirming that gene editing is a powerful tool to eradicate HIV infection, this work highlights that, to achieve this goal, the provirus has to be cleaved in several pieces and the infected cells treated with antiviral therapy before and after editing.

microbiology↗

bioRxiv2020

Intestinal receptor of SARS-CoV-2 in inflamed IBD tissue is downregulated by HNF4A in ileum and upregulated by interferon regulating factors in colon

Patients with IBD are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the effect of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD. We collected (un)inflamed mucosal biopsies from CD (n=193) and UC (n=158) patients, and 51 matched non-IBD controls for RNA sequencing, differential gene expression and co-expression analysis. Organoids from UC patients were subjected to an inflammatory mix and processed for RNA sequencing. Transmural ileal biopsies were processed for single-cell (sc) sequencing. Publicly available colonic sc-RNA sequencing data, and microarrays from tissue pre/post anti-TNF therapy, were analyzed. In inflamed CD ileum, ACE2 was significantly decreased compared to control ileum (p=4.6E-07), whereas colonic ACE2 expression was higher in inflamed colon of CD/UC compared to control (p=8.3E-03; p=1.9E-03). Sc-RNA sequencing confirmed this ACE2 dysregulation, and exclusive epithelial ACE2 expression. Network analyses highlighted HNF4A as key regulator of ileal ACE2, while pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids (p=1.7E-02), not in non-IBD controls (p=9.1E-01). Anti-TNF therapy restored colonic ACE2 dysregulation in responders. Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing effects in ileum and colon. HNF4A, an IBD susceptibility gene, is an important upstream regulator of ACE2 in ileum, whereas interferon signaling dominates in colon. Our data support the importance of adequate control of IBD in order to reduce risk of (complicated) COVID-19.

genomics↗

bioRxiv2020

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of resolution of inflammation but the mechanisms underlying their mucosal healing capacity remains elusive. Here, we describe a subset of E prostanoid receptor 4 (EP4) expressing intestinal macrophages with mucosal healing properties both in human and mice. Notably, Csf1r-iCre EP4-fl/fl mice showed defective mucosal healing and intestinal epithelial barrier regeneration in a dextran sodium sulfate-induced colitis model. Mechanistically, an increased mucosal level of prostaglandin E2 (PGE2) triggers the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in monocyte-derived EP4+ macrophages via MAPKs. Subsequently, CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during the resolution phase of colitis. Thus, EP4+ intestinal macrophages are essential for the support of the intestinal stem cell niche and for the regeneration of the injured epithelium. One Sentence SummaryProstaglandin E2 licenses E-type prostanoid receptor 4 intestinal macrophage regenerative capacity promoting mucosal healing via the secretion of CXCL1

immunology↗

bioRxiv2019

Dendritic cells require TMEM176A/B ion channels for optimal MHC II antigen presentation to naive CD4+ T cells

Intracellular ion fluxes emerge as critical actors of immunoregulation but still remain poorly explored. Here we investigated the role of the redundant cation channels TMEM176A and TMEM176B (TMEM176A/B) in ROR{gamma}t+ cells and conventional dendritic cells (cDCs) using germline and conditional double knock-out (DKO) mice. While Tmem176a/b appeared surprisingly dispensable for the protective function of Th17 and group 3 innate lymphoid cells (ILC3s) in the intestinal mucosa, we found that they were required in cDCs for optimal antigen processing and presentation to CD4+ T cells. Using a real-time imaging method, we show that TMEM176A/B accumulate in dynamic post-Golgi vesicles preferentially linked to the late endolysosomal system and strongly colocalize with HLA-DM. Together, our results suggest that TMEM176A/B ion channels play a direct role in the MHC II compartment (MIIC) of DCs for the fine regulation of antigen presentation and naive CD4+ T cell priming.

immunology↗