# NLRP3 inflammasome-mediated platelet hyperreactivity in sickle cell mice is targetable by BTK inhibition

## TL;DR

This study shows that inhibiting BTK can reduce platelet hyperreactivity in sickle cell disease mice by targeting the NLRP3 inflammasome.

## Contribution

The study demonstrates that BTK inhibition can target NLRP3 inflammasome-mediated platelet hyperreactivity in sickle cell disease.

## Key findings

- Platelet function assays in SCD mice show elevated responses reduced by NLRP3 or BTK inhibitors.
- BTK inhibition with ibrutinib reduces platelet hyperreactivity in SCD mice.
- Nigericin partially reverses the effects of ibrutinib on platelet function.

## Abstract

The platelet nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome is upregulated in sickle cell disease (SCD) and promotes platelet aggregation. We previously identified Bruton tyrosine kinase (BTK) as a critical regulator of the platelet NLRP3 inflammasome. However, whether NLRP3 contributes to platelet function beyond aggregation in SCD and whether these effects can be modulated through BTK inhibition, has been incompletely understood. Here, we show that platelet secretion, platelet spreading, platelet aggregation, and in vitro thrombus formation in response to collagen are elevated in SCD mice and are reduced following treatment of mice with the NLRP3 inhibitor MCC950 or the BTK inhibitor ibrutinib. The NLRP3 activator nigericin partially reversed the inhibitory effects of ibrutinib across all platelet function assays. Together, we identify the NLRP3 inflammasome as a critical mediator of platelet hyperreactivity in SCD mice, which can be targeted via BTK inhibition.