TY - JOUR T1 - Steroid hormone catabolites activate the pyrin inflammasome through a non-canonical mechanism JF - bioRxiv DO - 10.1101/2021.10.29.466454 SP - 2021.10.29.466454 AU - Flora Magnotti AU - Daria Chirita AU - Sarah Dalmon AU - Amandine Martin AU - Pauline Bronnec AU - Jeremy Sousa AU - Olivier Helynck AU - Wonyong Lee AU - Daniel Kastner AU - Jae Jin Chae AU - Michael F. McDermott AU - Alexandre Belot AU - Michel Popoff AU - Pascal Sève AU - Sophie Georgin-Lavialle AU - Hélène Munier-Lehmann AU - Tu Anh Tran AU - Ellen De Langhe AU - Carine Wouters AU - Yvan Jamilloux AU - Thomas Henry Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/29/2021.10.29.466454.abstract N2 - The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defences against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identified etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step-2 activators. High concentrations of these metabolites fully and rapidly activated pyrin, in a human-specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases (PAAND and FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, displayed increased responses to these metabolites. This study provides a new perspective on pyrin activation, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the “steroid fever” described in the late 1950s, upon steroid injection in humans.Competing Interest StatementThe authors have declared no competing interest. ER -