Biology subjects

Sanzo-Machuca, A.

Publications and source records attributed to Sanzo-Machuca, A..

6 recordsLinked to original sources

bioRxiv2026

Aryl hydrocarbon receptor (AhR) restrains the maintenance and acquisition of the anti-inflammatory identity of monocyte-derived macrophages.

The Aryl hydrocarbon receptor (AhR) is an essential environmental sensor bridging metabolic cues with immune regulation, yet its precise role in defining human monocyte-derived macrophage identity remains unclear. Here, we demonstrate that AhR functions as a critical transcriptional rheostat that selectively restrains the anti-inflammatory and pro-fibrotic identity of M-CSF-dependent monocyte-derived macrophages (M-Mac). Integrated ChIP-Seq and transcriptomic profiling revealed that AhR activity is enriched in M-Mac in a MAFB-dependent manner, directly occupying regulatory regions of core M-Mac identity genes, including CD163, LGMN, and IL10. Unexpectedly, siRNA-mediated knockdown and CRISPR/Cas9 ablation demonstrated that AhR primarily functions as a repressor; its deficiency accelerated and exacerbated the acquisition of a "resident-like" (LYVE1+/FOLR2+) and pro-fibrotic phenotype. Functionally, AhR restricted the M-Mac anti-inflammatory response to TLR7 ligation, and limited an overly tolerogenic profile during M-Mac-driven T-cell responses. Pharmacological modulation using the endogenous ligand FICZ and the antagonist SR1 confirmed that AhR activity limits the magnitude of the MAFB-driven program and the autocrine IL-10 signaling axis. Collectively, these findings establish AhR as a fundamental checkpoint that prevents macrophages from acquiring an excessive anti-inflammatory state, thereby ensuring balanced responses essential for tissue homeostasis and immune surveillance.

immunology↗

bioRxiv2026

The Human Gut Cell Atlas v1.0: A Unified, Community-BuiltReference of Cellular Diversity Across the Gut

Single-cell RNA-sequencing (scRNA-seq) studies have transformed our understanding of cellular diversity in the human intestine, but differences in anatomical sampling, experimental processing and cell-type nomenclature limit comparison across datasets. Here, we present the Human Gut Cell Atlas (HGCA) V1, a community-curated reference of 944,390 healthy and disease-adjacent intestinal cells from 502 samples, 265 donors and 24 landmark studies, linked to detailed anatomical, clinical, and technical metadata. As this metadata is of critical importance to human biology, we developed MetaManager, an open source data management framework for standardized metadata collection and tracking. A five-level consensus taxonomy resolves 94 homeostatic cell identities and enables transferrable, high-resolution annotation of new gut datasets. By assembling cell identity, sampling metadata, and independent spatial validation, intestinal segment and radial tissue depth were revealed to systematically shape cellular composition and transcriptional state, enabling inference of the presence of sampling-dependent tissue niches, including lymphoid follicles. Reference mapping accurately and rapidly recovered cohort-level Crohn's disease and treatment signatures without de novo annotation, while mapping human intestinal organoids quantified cell-type-specific identity, regional specification, maturation, and transcriptional fidelity to native tissue. The HGCA V1 provides a standardized cellular, anatomical coordinate, and metadata system for reproducible, high-quality analysis of intestinal biology across healthy tissue, disease-associated remodelling, and experimental models, providing a continuously evolving community reference for cumulative discovery in human intestinal biology.

systems biology↗

bioRxiv2026

A JAK-STAT-activated myeloid hub at ulceration sites underlies resistance to anti-TNF therapy in Crohn's disease

Despite major advances in immunotherapies, durable disease control in immune-mediated inflammatory diseases (IMIDs) is frequently limited by resistance driven by maladaptive immune programs, resulting in progressive tissue damage. Myeloid cells are central effectors across IMIDs, including inflammatory bowel disease (IBD), yet how discrete myeloid states govern disease progression and therapeutic response remains incompletely defined. Here, using integrative single-cell transcriptomic and molecular analyses of inflamed human ileum in Crohns disease (CD), we identify combinatorial transcriptional programs that revealed previously unrecognized axes of monocyte-macrophage (mo-mac) heterogeneity. These myeloid states and programs were conserved and validated across multiple independent cohorts. We delineate a pathogenic mo-mac subset, interferon-associated inflammatory monocytes (IFIM), shaped by convergent NF-{kappa}B and IFN{gamma} signaling and enriched in advanced disease. Baseline abundance of IFIM programs predicted resistance to anti-TNF therapy and severe postoperative recurrence, with IFIM-derived ligands sustaining epithelial injury. IFIM exhibited robust JAK-STAT activation, indicating susceptibility to JAK inhibition with clinically approved agents, including upadacitinib. Exemplified by IFIM-driven inflammation, these findings identify pathogenic myeloid state remodeling as a molecular basis of anti-TNF resistance and provide a framework for mechanism-guided therapeutic strategies across chronic inflammatory diseases.

immunology↗

bioRxiv2025

TL1A-activated T cells remodel the rectal mucosa in Crohn's disease patients with perianal fistulizing disease

BackgroundPerianal fistulizing disease (PFD) is a complication that affects about 20% of Crohns disease (CD) patients whose etiology remains unknown. ObjectivesTo identify predisposing events driving fistula formation. DesignRectal biopsies from CD patients with or without PFD (CD+PFD and CD, respectively; n=31) were collected and subjected to single-cell RNA sequencing (scRNA-seq). Functional analyses were conducted using peripheral CD3+ T cells, intestinal tissue explants, primary fibroblasts and 2D-epithelial monolayer cell cultures. ResultsThe rectal mucosa of CD+PFD patients is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by TL1A activation in CD4+ T cells. We identified lymphotoxin beta (LTB or its functional heterotrimer LT1{beta}2) as a novel mediator downstream of TL1A that, along with IL-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes, transcriptomic rewiring of the lamina propria S1 fibroblasts, and an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LT1{beta}2 and IL-22 occurs independently of TNF signaling, revealing a new TL1A-LT1{beta}2/IL-22 axis that remains active under anti-TNF therapy. ConclusionOur findings revealed unique cellular alterations in the rectum of CD patients with PFD, highlighting the previously unrecognized involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.

immunology↗

bioRxiv2024

Understanding the mechanisms underlying the lack of response to Janus kinase inhibition in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. About one-third of UC patients failed to respond to available drugs, including tofacitinib, a broad Janus kinase (JAK) inhibitor. However, the mechanisms underlying patient response or resistance to oral JAK inhibitors remain unknown. To elucidate the molecular and cellular pathways activated by tofacitinib in responder and non-responder patients, we generated a longitudinal single-cell RNA sequence dataset profiling both immune and non-immune cell populations from colonic biopsies of UC patients. Our analysis revealed that responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Longitudinal comparisons showed that disease progression in non-responders was associated with increased abundance and enhanced activation of macrophages and fibroblasts. Our data suggest that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells, and we identified IL-10-dependent macrophages as a cellular subset contributing to this resistance.

immunology↗

bioRxiv2023

Interpretable Inflammation Landscape of Circulating Immune cells

Inflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >6.5 million peripheral blood mononuclear cells from 1047 patients and 19 diseases allowed us to learn a comprehensive model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of immune-mediated diseases, acute and chronic inflammatory diseases, infection and solid tumors, and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered analysis, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting discriminative inflammation-related genes to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing pathologic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient diagnosis.

immunology↗