KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation

Ran, Li1,2,3,4; Ye, Tao1,2,3,4; Erbs, Eric1,2,3,4; Ehl, Stephan5,6; Spassky, Nathalie7; Sumara, Izabela1,2,3,4; Zhang, Zhirong1,2,3,4,9; Ricci, Romeo1,2,3,4,8

2023-12-22

10.1126/sciimmunol.adf4699

SCIENCE IMMUNOLOGY   影响因子和分区

2470-9468

Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin-associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop autoinflammation triggered by nonantigenic cues such as from the environment. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowered the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increased NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protected mice from gouty arthritis. Mechanistically, activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux and promotes NLRP3 inflammasome activation. Activation of PIEZO signaling was sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Last, pharmacological inhibition of KCNN4 alleviated autoinflammation in cells of patients with CAPS and in mice bearing a CAPS mutation. Thus, PIEZO-dependent mechanical inputs boost inflammation in NLRP3-dependent diseases, including CAPS.

SCI

英语

通讯

Agence Nationale de la Recherche (ANR)["AAPG 2017 LY SODIABETES","AAPG 2022 IL1PYR","AAPG 2023 ENDOFLAMMA SOME"] ; Fondation de Recherche Medicale (FRM)-Program: Equipe FRM[EQU201903007859] ; ANR["ANR-10-LABX-0030-INRT","ANR-11-INBS-0009-INGE","ANR-20-CE45-0019","ANR-21-CE16-0016","ANR-22-CE16"] ; Fondation pour la Recherche Medicale[FRM EQU202103012767] ; European Research Council (ERC Consolidator grant)[647466] ; Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy["CIBSS-EXC-21899","390939984"] ; Agence Nationale de la Recherche (ANR)["ANR-20-CE45-0019","ANR-21-CE16-0016"]

Immunology

Immunology

WOS:001161708600001

AMER ASSOC ADVANCEMENT SCIENCE

Web of Science

1.Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France
2.Ctr Natl Rech Sci, UMR7104, Illkirch Graffenstaden, France
3.Inst Natl Sante & Rech Med, U964, Illkirch Graffenstaden, France
4.Univ Strasbourg, Illkirch Graffenstaden, France
5.Univ Freiburg, Ctr Chron Immunodeficiency, Med Ctr, Inst Immunodeficiency,Fac Med, Freiburg, Germany
6.Albert Ludwigs Univ, CIBSS Ctr Integrat Biol Signaling Studies, Freiburg, Germany
7.PSL Res Univ, Ecole Normale Super, Inst Biol, INSERM,CNRS,Ecole Normale Super IBENS, Paris, France
8.Nouvel Hop Civil, Lab Biochim & Biol Mol, Strasbourg, France
9.Southern Univ Sci & Technol, Sch Med, Dept Biochem, Shenzhen 518055, Peoples R China

Ran, Li,Ye, Tao,Erbs, Eric,et al. KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation[J]. SCIENCE IMMUNOLOGY,2023,8(90).

Ran, Li.,Ye, Tao.,Erbs, Eric.,Ehl, Stephan.,Spassky, Nathalie.,...&Ricci, Romeo.(2023).KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation.SCIENCE IMMUNOLOGY,8(90).

Ran, Li,et al."KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation".SCIENCE IMMUNOLOGY 8.90(2023).