Steroid hormone catabolites activate the pyrin inflammasome through a non-canonical mechanism

Flora Magnotti (1) , Daria Chirita (1) , Sarah Dalmon (1) , Amandine Martin (1) , Pauline Bronnec (1) , Jeremy Sousa (1) , Olivier Helynck (2, 3) , Wonyong Lee (4) , Daniel L Kastner (4) , Jae Jin Chae (4) , Michael F Mcdermott (5) , Alexandre Belot (1, 6, 7) , Michel Popoff (8) , Pascal Sève (7) , Sophie Georgin-Lavialle (9) , Hélène Munier-Lehmann (2, 3) , Tu Anh Tran (10) , Ellen de Langhe (11, 12) , Carine Wouters (11, 12) , Yvan Jamilloux (1, 6, 7, 13) , Thomas Henry (1)

1 CIRI - Centre International de Recherche en Infectiologie
2 Chimie et Biocatalyse
3 UPCité - Université Paris Cité
4 NIH - National Institutes of Health [Bethesda, MD, USA]
5 University of Leeds
6 LIFe - Lyon Immunopathology Federation
7 HCL - Hospices Civils de Lyon
8 Toxines bactériennes - Bacterial Toxins
9 CRSA - Centre de Recherche Saint-Antoine
10 CHU Nîmes - Hôpital Universitaire Carémeau [Nîmes]
11 University Hospitals Leuven [Leuven]
12 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
13 UCBL - Université Claude Bernard Lyon 1

The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses 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 identifies 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 activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, 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.

Mots clés: B30.2; CP: Immunology; CP: Molecular biology; PAAND; autoinflammatory disease; catabolite; familial Mediterranean fever; inflammasome; pregnanolone; progesterone; pyrin; steroid

Domaines: Immunologie

Flora Magnotti, Daria Chirita, Sarah Dalmon, Amandine Martin, Pauline Bronnec, et al.. Steroid hormone catabolites activate the pyrin inflammasome through a non-canonical mechanism. Cell Reports, 2022, 41 (2), pp.111472. ⟨10.1016/j.celrep.2022.111472⟩. ⟨hal-03811426⟩