The pyrin inflammasome is an immune complex known for its importance in antibacterial responses. The study published in the journal Cell Reports changes this paradigm by showing that pyrin is activated by derivatives of the sex hormones progesterone and testosterone, endogenous molecules produced in our body, without association with a bacterial infection.

Abstract

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.

Reference: Steroid hormone catabolites activate the pyrin inflammasome through a non-canonical mechanism. Magnotti F, Chirita D, Dalmon S, Martin A, Bronnec P, Sousa J, Helynck O, Lee W, Kastner DL, Chae JJ, McDermott MF, Belot A, Popoff M, Sève P, Georgin-Lavialle S, Munier-Lehmann H, Tran TA, De Langhe E, Wouters C, Jamilloux Y, Henry T Cell Reports, October 11, 2022.
DOI: 10.1016/j.celrep.2022.111472