Biology subjects

Pages, E.

Publications and source records attributed to Pages, E..

3 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↗

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

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↗