Article Dans Une Revue Blood Année : 2024

Reduction of mortality, cardiac damage, and cerebral damage by IL-1 inhibition in a murine model of TTP

Romain Muller
Raphaël Cauchois
Marie Lagarde
Sandrine Roffino
Cécile Genovesio
  • Fonction : Auteur
Samantha Fernandez
  • Fonction : Auteur
Guillaume Hache
Benjamin Guillet
Yéter Kara
  • Fonction : Auteur
Marion Marlinge
Pascale Poullin
Gilles Kaplanski

Résumé

Abstract Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in von Willebrand factor cleavage resulting in capillary microthrombus formation and ischemic organ damage. Interleukin-1 (IL-1) has been shown to drive sterile inflammation after ischemia and could play an essential contribution to postischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasma IL-1 concentrations in patients with TTP and controls. Patients with TTP exhibited elevated plasma IL-1α and -1β concentrations, which correlated with disease course and survival. In a mouse model of TTP, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P < .001). Anakinra significantly decreased TTP-induced cardiac damage as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]fluorodeoxyglucose positron emission tomography of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damage evaluated through blood PS100b concentrations, nuclear imaging, and histology. We finally showed that IL-1α and -1β trigger endothelial degranulation in vitro, leading to the release of von Willebrand factor. In conclusion, anakinra significantly reduced TTP mortality in a preclinical model of the disease by inhibiting both endothelial degranulation and postischemic inflammation, supporting further evaluations in humans.

Dates et versions

hal-04654298 , version 1 (19-07-2024)

Identifiants

Citer

Romain Muller, Raphaël Cauchois, Marie Lagarde, Sandrine Roffino, Cécile Genovesio, et al.. Reduction of mortality, cardiac damage, and cerebral damage by IL-1 inhibition in a murine model of TTP. Blood, 2024, 143 (26), pp.2791-2803. ⟨10.1182/blood.2023021974⟩. ⟨hal-04654298⟩
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