Combining new imaging approaches and various genetic models, we showed that exposure to domestic allergens trigger the activation of MC-nociceptor functional knots in the skin, which represents a key early event regulating the development of allergic skin inflammation. We used an AD-like mouse model displaying moderate to severe AD-like lesions and featuring pathological traits similar to human AD. In vivo ablation of TRPV1+ neurons, deletion of Tac1 gene or genetic inactivation of the MC-restricted cationic receptor MRGPRB2 significantly reduced the development of allergic skin inflammation and its associated features, highlighting a substantial role for MRGPRB2+ MCs and Substance P-producing sensory neurons in the pathology. Using intravital imaging in living genetically modified mice, we also observed that activated TRPV1+ Tac1+ nociceptors induced the degranulation of contiguous MCs in the skin, through the release of substance P and consequent activation of MRGPRB2. These results were published in Nature Immunology in the article entitled ‘House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation’. In continuity with these results, we have initiated the design of new therapeutic molecules in order to hopefully treat AD in humans.
We then further characterized those MCs in mice and humans across organs. Through whole-tissue imaging and single-cell RNA sequencing, we identified two distinct MC populations in mice: MrgprB2+ connective tissue MCs, which develop in utero independent of bone marrow, and MrgprB2neg mucosal MCs, developing postnatally and renewed by bone marrow progenitors. In humans, seven MC subsets (MC1–6) were identified across 12 organs, each with distinct transcriptomic profiles. This study reveals significant diversity of MC subtypes in mice and humans. These findings were published in 2023 in the "Journal of Experimental Medicine" and were entitled: "Landscape of mast cells across organs in mice and humans".
Finally, in order to investigate neuroimmune interactions in human samples we generated a new imaging method. Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. We developed MANTIS (Multiplex 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. On the basis of phenotype attribution matrices coupled to α-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 nonrandom 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. These findings were published in "Science Advances" in 2023 and are entitled "3D deconvolution of human skin immune architecture with Multiplex Annotated Tissue Imaging System".
