Biology subjects

Miraldi, E.

Publications and source records attributed to Miraldi, E..

5 recordsLinked to original sources

bioRxiv2025

Epithelial-intrinsic nitric oxide synthase 2 sustains host-microbiota dynamics that promote colitis

The microbiota influence disease pathogenesis and treatment, however we have limited ability to assess patient status in relation to the microbiota. Here we find that the nitric oxide generating enzyme, nitric oxide synthase 2 (Nos2), is transcriptionally primed in intestinal epithelial cells (IECs), as opposed to immune cells, in inflammatory bowel disease (IBD) patients. Generation of IEC-specific Nos2 knockout mice revealed that epithelial Nos2 activity promoted susceptibility to intestinal disease and sustained a colitogenic microbiota. Epithelial Nos2 increased levels of nitric oxide-derived nitrates and nitrate-metabolizing bacteria in the intestine. Unexpectedly, extra-intestinal nitrates also reflected IEC-intrinsic Nos2 expression, and systemic nitrate concentrations in patients paralleled intestinal Nos2 activation. In fact, temporally inhibiting epithelial Nos2 was sufficient to alter intestinal nitrate homeostasis and inflammation in mice, as well as restrict nitrate production by human intestinal organoids. These data reveal that epithelial nitric oxide metabolism directs host-microbiota dynamics that can alter disease and that monitoring and targeting this axis may benefit patients with IBD.

immunology↗

bioRxiv2025

Macrophages drive a fibrogenic gene program of periductal fibroblasts in pediatric primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is an autoimmune, cholestatic liver disease characterized by inflammation and fibrosis surrounding bile ducts. The cellular crosstalk driving periductal fibrosis remains poorly defined. This study applied a multi-omics approach integrating MERSCOPE spatial transcriptomics, bulk RNA-seq, and SomaScan proteomics to characterize fibrotic periductal regions and their cell-cell communications. Macrophages (MP) expressing moderate-to-high CD163 were found co-localized with cholangiocytes, T cells, and collagen-producing hepatic stellate cells (HSC). Cell niche analysis identified periductal regions with elevated fibrotic signals, in which cell-cell communication analysis revealed MP-HSC interactions involving 17 fibrotic driver genes in MP (e.g., IFNGR1, CSF1R, CD163) and six fibrotic effector genes in HSC (e.g., COL1A2, VCAN, MMP2). In validation analyses, bulk RNA-seq data showed higher driver and effector gene scores in PSC with established fibrosis compared to early-stage PSC and autoimmune hepatitis (AIH). Plasma proteins encoded by MP driver genes were elevated in autoimmune liver disease (AILD) and in patients with elevated ([≥]3.29 kPa) liver stiffness on MR elastography. These findings suggest that macrophages engage in localized crosstalk with HSC, activating fibrotic gene programs and contributing to periductal fibrosis in PSC, thereby identifying potential molecular targets for therapeutic intervention.

immunology↗

bioRxiv2024

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

immunology↗

bioRxiv2023

Elevated CD153 Expression on Aged T Follicular Helper Cell is Vital for B cell Responses

Our recent data showed that an aberrant IL-10-producing T follicular helper population (Tfh10) accumulates dramatically with age and is associated with age-related declines in vaccine responsiveness. Through single cell gene expression and chromatin accessibility analysis of IL-10+ and IL-10- memory CD4+ T cells from young and aged mice, we identified increased expression of CD153 on aged Tfh and Tfh10 cells. Mechanistically, we linked inflammaging (increased IL-6 levels) to elevated CD153 expression of Tfh cells through c-Maf. Surprisingly, blockade of CD153 in aged mice significantly reduced their vaccine-driven antibody response, which was associated with decreased expression of ICOS on antigen-specific Tfh cells. Combined, these data show that an IL-6/c-Maf/CD153 circuit is critical for maintaining ICOS expression. Thus, although overall Tfh-mediated B cell responses are reduced in the context of vaccines and aging, our data suggest that elevated expression of CD153 on Tfh cells potentiates the remaining Tfh function in aged mice.

immunology↗

bioRxiv2018

The impact of endogenous retroviruses on nuclear organization and gene expression

BackgroundThe organization of chromatin in the nucleus plays an essential role in gene regulation. When considering the mammalian genome it is important to take into account that about half of the DNA is comprised of transposable elements. Given their repetitive nature, reads associated with these elements are generally discarded or randomly distributed among elements of the same type in genome-wide analyses. Thus, it is challenging to identify the activities and properties of individual transposons. As a result, we only have a partial understanding of how transposons contribute to chromatin folding and how they impact gene regulation.\n\nResultsUsing adapted PCR and Capture-based chromosome conformation capture (3C) approaches, collectively called 4Tran, we take advantage of the repetitive nature of transposons to capture interactions from multiple copies of endogenous retrovirus (ERVs) in the human and mouse genomes. With 4Tran-PCR, reads are selectively mapped to unique regions in the genome. This enables the identification of TE interaction profiles for individual ERV families and integration events specific to particular genomes. With this approach we demonstrate that transposons engage in long-range intra-chromosomal interactions guided by the separation of chromosomes into A and B compartments as well as topologically associated domains (TADs). In contrast to 4Tran-PCR, Capture-4Tran can uniquely identify both ends of an interaction that involve retroviral repeat sequences, providing a powerful tool for uncovering the individual TE insertions that interact with, and potentially regulate target genes.\n\nConclusions4Tran provides new insight into the manner in which transposons contribute to chromosome architecture and identifies target genes that transposable elements can potentially control.

genomics↗