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Fibroblast S1PR2 Amplifies NLRP3 Inflammasome Activation Under Pressure Overload
Caixia Zhou1, Zhihao Liu1, Zhiru Wang1
1State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, China (C.Z., Z.L., Z.W., Z.C., Q.W., X.F., X.C., J.L., Y.Z., L.Z.).
Hypertension (Dallas, Tex. : 1979)
|July 20, 2026
Summary
Cardiac fibroblasts, not just immune cells, activate the NLRP3 inflammasome in pressure overload heart failure. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling in these cells drives mitochondrial damage and inflammation.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Biology
Background:
- NLRP3 inflammasome activation is linked to pressure overload-induced heart failure.
- Previous research focused on cardiomyocytes and immune cells, neglecting cardiac fibroblasts.
- The role of cardiac fibroblasts in NLRP3 inflammasome activation under pressure overload is unclear.
Purpose of the Study:
- To investigate the role of cardiac fibroblasts in NLRP3 inflammasome activation during pressure overload.
- To identify the upstream regulator of fibroblast NLRP3 inflammasome activation in the pressure-overloaded heart.
Main Methods:
- Analysis of single-cell transcriptomic data from human and murine hearts.
- Utilized fibroblast-specific Nlrp3-knockout mice and S1pr2 loss- and gain-of-function models.
- Induced pressure overload using transverse aortic constriction.
Main Results:
- Cardiac fibroblasts are key effectors of NLRP3 inflammasome activation under pressure overload.
- Fibroblast NLRP3 deficiency attenuated cardiac hypertrophy and inflammation.
- Sphingosine-1-phosphate receptor 2 (S1PR2) was identified as a critical upstream regulator, with its signaling promoting mitochondrial damage and NLRP3 activation.
Conclusions:
- Cardiac fibroblasts are a major source of NLRP3 inflammasome activation in pressure overload.
- Fibroblast S1PR2 signaling connects mitochondrial dysfunction to inflammasome activation.
- This pathway represents a novel proinflammatory axis exacerbating heart failure.
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