Cell-intrinsic steroidogenesis regulates mast cell function.

Steroid hormones are well-known regulators of mast cell function, but whether mast cells themselves produce steroids de novo and influences their effector function has remained unknown. Here, we show that mast cells constitutively express the steroidogenic enzyme cytochrome P450 family 11 subfamily A member 1 (Cyp11a1) and produce pregnenolone. Cyp11a1 expression was detected across tissue-resident mast cells from multiple organs, was conserved in human mast cells, and was enhanced by interleukin-3 signaling and after activation. We identified Cyp11a1 as a Gata2-dependent, superenhancer-associated mast cell gene, placing steroidogenesis within the core mast cell transcriptional program. Loss of Cyp11a1 altered transcriptomic and proteomic programs in mast cells, with effects on pathways linked to cell growth, immune signaling, and effector function. Functionally, Cyp11a1-deficient mast cells showed increased degranulation in response to both immunoglobulin E (IgE)-dependent and IgE-independent stimulation. In vivo, loss of Cyp11a1 reduced mast cell abundance in several tissues but exacerbated passive cutaneous anaphylaxis. These findings identify cell-intrinsic steroidogenesis as a regulatory pathway that restrains mast cell activation and anaphylactic responses.