Biology subjects

Gaudenzio, N.

Publications and source records attributed to Gaudenzio, N..

7 recordsLinked to original sources

bioRxiv2026

A TAK1-Driven NLRP1 Inflammasome Pathway Revealed by Phosphatase-Targeting Environmental Toxins

Human NLRP1 is highly sensitive to phosphorylation-dependent activation, indicating a need for tight phosphatase control to prevent excessive inflammasome activity. In this study, we identified the phosphatases PP1 and PP2A as negative regulators of the NLRP1 inflammasome in human keratinocytes. Accordingly, exposure to the environmental toxins Dinophysistoxin, Okadaic acid, and Cantharidin, which inhibit PP1 and PP2A, triggered NLRP1 inflammasome activation. Notably, this toxin-induced activation process relied on hyperactivation of the MAP3 kinase TAK1. Mechanistically, both TAK1 and its downstream effectors p38 kinases phosphorylated and activated the NLRP1 inflammasome. Further studies underscored that TAK1 also contributed to the NLRP1 inflammasome activation during double-stranded RNA stimulation and viral infection. Finally, human native skins exposed to environmental toxins underlined the role of the PP1/PP2A-regulated TAK1/p38 axis in the development of skin dermatitis. Thus, these findings reveal a novel pathway of phosphorylation-driven NLRP1 activation and expand our understanding of its regulation in epithelial immunity. One Sentence SummaryPP1/PP2A phosphatases restrict TAK1-driven NLRP1 inflammasome response. O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/701233v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@128de37org.highwire.dtl.DTLVardef@151fbdorg.highwire.dtl.DTLVardef@d6b98aorg.highwire.dtl.DTLVardef@12f419d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Schematic representation of the phosphorylation-driven hNLRP1 inflammasome response upon exposure to environmental toxins and to dsRNA/viral infection. C_FIG

immunology↗

bioRxiv2025

Local B cell maturation and mast cell regulation of choroid plexus function in early life.

Postnatal development is a critical period for the maturation of the nervous and immune systems. The choroid plexus (CP) within the brain ventricles guides brain development through the production of cerebrospinal fluid and responds to stimuli from its local immune microenvironment. Here, using single-cell sequencing, we chart the establishment of the immune niche within the CP from birth to adulthood. We demonstrate that the CP is an active site for the development of B cells from early pro-B cells to mature B cells. We also characterize a transient population of CP mast cells that is highly abundant in the perinatal period. Single activation of these cells shortly after birth led to activation of serotonin-dependent secretion from the CP epithelial cells and resulted in cognitive impairment later in life. Our findings highlight the crucial nature of the CP as a neuroimmune interface, where cellular crosstalk regulates key functions of CP activity, thereby guiding brain development.

immunology↗

bioRxiv2025

Identification of a unique TUBB3+ cell population in the tuberculosis granuloma

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading cause of mortality worldwide. Granulomas, hallmark structures of TB in the lungs and other infected tissues, are critical sites of host-pathogen interactions, yet their full cellular composition is not completely understood. Here, we identify a previously unrecognized {beta}3-tubulin (TUBB3)-positive cell population within TB granulomas in mice, guinea pigs, non-human primates, and TB patients. TUBB3 is a well-established pan-neuronal marker, yet these TUBB3+ cells are distinct from typical pulmonary resident cells and leukocytes. They exhibit a branched, elongated morphology, which is suggestive of neuron-like features. Intriguingly, their appearance is independent of adaptive immunity and is also observed in viral and fungal infections, but not in asthma. Our findings suggest the existence of a neuro-immune component within granulomas that may influence TB pathogenesis. Further investigation into the origin, function, and signaling pathways of these TUBB3+ cells is required to clarify their identity and potential role in host defense, which could reveal novel therapeutic targets for TB and other pulmonary infections.

immunology↗

bioRxiv2023

Multi-modal profiling of biostabilized human skin modules reveals a coordinated ecosystem response to injected mRNA-1273 COVID-19 vaccine.

The field of vaccination is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials. Here we introduce VaxSkin, a flexible solution designed for the comprehensive monitoring of the natural human skin ecosystems response to vaccines over time. Based on bioengineering to repurpose surgical resections, it allows a comprehensive analysis of the response to vaccines at both organ and single-cell levels. Upon injection of the mRNA-1273 COVID-19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. We also found that the vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell-cell communications in surrounding immune cell subsets. Given its direct translational relevance, VaxSkin provides a multiscale vision of skin vaccination that could pave the way toward the development of new vaccination development strategies.

bioengineering↗

bioRxiv2023

Mast cell-derived BH4 is a critical mediator of postoperative pain

Postoperative pain affects most patients after major surgery and can transition to chronic pain. Here, we discovered that postoperative pain hypersensitivity correlated with markedly increased local levels of the metabolite BH4. Gene transcription and reporter mouse analyses after skin injury identified neutrophils, macrophages and mast cells as primary postoperative sources of GTP cyclohydrolase-1 (Gch1) expression, the rate-limiting enzyme in BH4 production. While specific Gch1 deficiency in neutrophils or macrophages had no effect, mice deficient in mast cells or mast cell-specific Gch1 showed drastically decreased postoperative pain after surgery. Skin injury induced the nociceptive neuropeptide substance P, which directly triggers the release of BH4-dependent serotonin in mouse and human mast cells. Substance P receptor blockade substantially ameliorated postoperative pain. Our findings underline the unique position of mast cells at the neuro-immune interface and highlight substance P-driven mast cell BH4 production as promising therapeutic targets for the treatment of postoperative pain.

immunology↗

bioRxiv2023

3-D deconvolution of human skin immune architecture with Multiplex Annotated Tissue Imaging System (MANTIS)

Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. Here we introduce MANTIS (Multiplexed Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically-designed for spatially-resolved immune phenotyping of the skin in experimental or clinical samples. Based on phenotype attribution matrices coupled to -shape algorithms, MANTIS projects a representative digital immune landscape, while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome or COVID-19-associated skin manifestations share common quantitative immune features, while displaying a non-random distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.

immunology↗

bioRxiv2021

T helper cell-licensed mast cells promote inflammatory Th17 cells

CD4+ T helper cells (Th) infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells particularly abundant in skin and mucosa. Here, we analyzed the interplay between human MCs and Th cells and, through the application of RNAseq and functional assays, showed that Th cells induced a specific transcriptomic program in helped MCs (named here MCTH) driving them toward an inflammatory phenotype. The gene signature of MCTH indicated that MCs helped by Th cell acquired in turn the capacity to regulate effector T cell response through wide-range of soluble and membrane ligands. Accordingly, we showed that MCTH promoted Th17 cells and notably an inflammatory subset of Th17, producing both IFN-{gamma} and GM-CSF, through a PGE2 and IL-1{beta} axis. Our findings demonstrate that activated effector/memory CD4+ T cells activate and instruct resting MCs toward a specific differentiated pro-inflammatory phenotype endowed with the capacity to speak back to effector T cells and to mold their functions.

immunology↗