Primitive Steroidogenesis in Mast Cells: A Novel Regulatory Mechanism for Mast Cell Function

Abstract

Mast cells, ancient immune sentinels, are crucial in immune responses, tissue homeostasis and inflammatory pathologies. This study unveils a previously unknown regulatory mechanism in mast cell biology: de novo steroidogenesis. Through comprehensive multi-omics analysis and functional assays, we demonstrate that mast cells express Cyp11a1 and produce pregnenolone, representing a primitive form of steroidogenesis. This cell-intrinsic steroidogenic pathway is essential for mast cell development, survival, and functional regulation. Genetic abrogation of mast cell steroidogenesis leads to exaggerated inflammatory and anaphylactic responses in vivo. Our integrative approach reveals extensive transcriptional and proteomic remodelling during mast cell regranulation, with steroidogenesis playing a pivotal role in coordinating recovery and tissue repair processes. We uncover significant sexual dimorphism in mast cell proteomes and a global uncoupling of transcriptional and translational programmes. These findings advance our understanding of mast cell physiology and provide a foundation for developing targeted therapies for mast cell-associated pathologies.

Note:
Funding Information: The work is supported by CRUK Career Development Fellowship (RCCFEL\100095), NSF-BIO/UKRI-BBSRC project grant (BB/V006126/1), MRC project grant (MR/V028995/1), CRUK Cambridge Centre Cancer Immunology Programme Pump Priming award, and CRUK CC MRes/PhD Studentship.

Declaration of Interests: The authors declare that they have no competing interests.

Ethics Approval Statement: All experimental protocols were conducted under the authorization of a UK Home Office Project License (PPL PP2448972) and received the necessary approval from the local institute’s Animal Welfare and Ethical Review Body, ensuring compliance with ethical standards and animal welfare considerations.

Keywords: Mast cell, Steroidogenesis, Steroid-signalling, Pregnenolone, Degranulation, Regranulation, Immune & Tissue Homeostasis, Inflammation, Allergy.