Mast Cells Are a Reservoir of NLRP1 in Human Skin.

NLRP1 is an inflammasome sensor protein expressed in barrier tissues of humans. Its activation in response to microbes or cellular stress triggers a cascade of molecular events, leading up to IL1β-driven inflammation and pyroptosis. Rare germline mutations of NLRP1 cause its persistent activation, resulting in autoinflammatory syndromes. Multiple self-healing palmoplantar carcinoma (MSPC) is one such syndrome, characterized by the appearance of recurrent keratoacanthomas (KAs) on the palms and soles. Here, we aimed to compare the subcellular localization of mutant NLRP1 in lesions from an MSPC patient to wild-type NLRP1 in non-MSPC-KAs and in skin from healthy donors. Using mass spectrometry, immunohistochemistry and immunoelectron tomography, we found that NLRP1 localized to mast cell granules in all MSPC lesions but also in healthy skin, a novel finding which implicates these cells in NLRP1-associated responses in human skin. Moreover, we found that mast cells expressing the A66V pathogenic variant of NLRP1 overpopulated MSPC-KAs, infiltrated the epidermis and degranulated, a behavior not seen in other lesions from this study. The released granules had the highest NLRP1 protein content and also contained NLRP3 and IL1β, suggesting the coexistence of inflammasome pathways within mast cells. Taken together, our findings propose cutaneous mast cells as a previously unrecognized NLRP1 reservoir in health and disease.