Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage

Yingting Hou; Hongbin He; Ming Ma; Rongbin Zhou

doi:10.3389/fimmu.2023.1128700

Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage

Front Immunol. 2023 Jun 8:14:1128700. doi: 10.3389/fimmu.2023.1128700. eCollection 2023.

Authors

Yingting Hou^{1

2}, Hongbin He¹, Ming Ma^{1

2}, Rongbin Zhou^{1

2}

Affiliations

¹ Center for Advanced Interdisciplinary Science and Biomedicine of Institute of Health and Medicine (IHM), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² The Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Abstract

NLRP3 is an important innate immune sensor that responses to various signals and forms the inflammasome complex, leading to IL-1β secretion and pyroptosis. Lysosomal damage has been implicated in NLRP3 inflammasome activation in response to crystals or particulates, but the mechanism remains unclear. We developed the small molecule library screening and found that apilimod, a lysosomal disruptor, is a selective and potent NLRP3 agonist. Apilimod promotes the NLRP3 inflammasome activation, IL-1β secretion, and pyroptosis. Mechanismically, while the activation of NLRP3 by apilimod is independent of potassium efflux and directly binding, apilimod triggers mitochondrial damage and lysosomal dysfunction. Furthermore, we found that apilimod induces TRPML1-dependent calcium flux in lysosomes, leading to mitochondrial damage and the NLRP3 inflammasome activation. Thus, our results revealed the pro-inflammasome activity of apilimod and the mechanism of calcium-dependent lysosome-mediated NLRP3 inflammasome activation.

Keywords: NLRP3 inflammasome; activation; apilimod; lysosome; mitochondria.

Publication types

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

MeSH terms

Calcium / metabolism
Carrier Proteins / metabolism
Inflammasomes* / metabolism
Lysosomes / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
apilimod
Calcium
Carrier Proteins

Grants and funding

This research was supported by the National Key Research and Development Program of China (grants 2019YFA0508503 and 2020YFA0509101), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB29030102), the National Natural Science Foundation of China (grants 81821001 and 82130107), the CAS Project for Young Scientists in Basic Research (YSBR-074), and the Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province (GXXT-2019-026).