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

Etiocholanolone Familial Mediterranean Fever / genetics Humans Inflammasomes / metabolism Mutation Pregnanolone Progesterone Pyrin / genetics Testosterone

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

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
11 10 2022

Historique:

received: 01 10 2021

revised: 18 06 2022

accepted: 16 09 2022

entrez: 12 10 2022

pubmed: 13 10 2022

medline: 15 10 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2022.111472 PMID: 36223753 PMC: PMC9626387

pubmed: 36223753

pii: S2211-1247(22)01322-5

doi: 10.1016/j.celrep.2022.111472

pmc: PMC9626387

mid: NIHMS1843395

pii:

doi:

Substances chimiques

Inflammasomes 0

MEFV protein, human 0

Pyrin 0

Testosterone 3XMK78S47O

Progesterone 4G7DS2Q64Y

Etiocholanolone 97CGB1M48I

Pregnanolone BXO86P3XXW

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

111472

Subventions

Organisme : Intramural NIH HHS

ID : Z01 AR041083

Pays : United States

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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