Mast cell tolerance in the skin microenvironment to commensal bacteria is controlled by fibroblasts

Activation and degranulation of mast cells (MCs) is an essential aspect of innate and adaptive immunity. Skin MCs, the most exposed to the external environment, are at risk of quickly degranulating with potentially se-vere consequences. Here, we define how MCs assume a tolerant phenotype via crosstalk with dermal fibro-blasts (dFBs) and how this phenotype reduces unnecessary inflammation when in contact with beneficial commensal bacteria. We explore the interaction of human MCs (HMCs) and dFBs in the human skin micro -environment and test how this interaction controls MC inflammatory response by inhibiting the nuclear factor kB (NF-kB) pathway. We show that the extracellular matrix hyaluronic acid, as the activator of the regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor a-induced protein 3 (TNFAIP3), is respon-sible for the reduced HMC response to commensal bacteria. The role of hyaluronic acid as an anti-inflamma-tory ligand on MCs opens new avenues for the potential treatment of inflammatory and allergic disorders.