International immunopharmacology · 2026
Succinate/SUCNR1 signaling amplifies macrophage inflammatory priming in atherosclerosis through the ERK-MYD88 axis.
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Li Zhe, Zhang Xinling, Yan Chunyuan, Wang Xuejun, Gao Mei, Hou Yinglong, Xu Jingwen
Аннотация
BACKGROUND: Atherosclerosis remains a major cause of cardiovascular events, with macrophage-driven inflammation contributing to disease progression. This study investigated whether succinate receptor 1 (SUCNR1) functions as a disease-relevant signaling node in atherosclerosis.
METHODS: THP-1-derived macrophages, Sucnr1-deficient bone marrow-derived macrophages, and Apoe-/-/Sucnr1-/- mice were used to examine succinate/SUCNR1 signaling. Pharmacological inhibition, MYD88 overexpression, proteomics, qRT-PCR, Western blotting, co-immunoprecipitation, immunofluorescence, ELISA, and histology were performed.
RESULTS: SUCNR1 inhibition suppressed macrophage inflammatory signaling and reduced NLRP3 and IL-1β more prominently than NF-κB activation. Proteomics identified MYD88 as a downstream component. Succinate mainly increased MYD88 expression alone but strongly amplified inflammatory responses under low-dose LPS stimulation, indicating a priming effect. MYD88 overexpression restored NF-κB, NLRP3, and IL-1β responses and recovered MYD88-associated proximal signaling complexes during SUCNR1 inhibition. Mechanistically, succinate rapidly induced ERK phosphorylation, and ERK blockade reduced MYD88 mRNA and protein, placing ERK upstream of MYD88. In Apoe-/- mice, Sucnr1 deficiency attenuated plaque burden, lipid deposition, macrophage infiltration, and fibrotic remodeling, whereas MYD88 restoration partially reversed these protective effects.
CONCLUSION: Succinate/SUCNR1 signaling promotes atherosclerotic inflammation in part through ERK-dependent MYD88 upregulation, supporting SUCNR1 as a pharmacologically targetable node in immunometabolic vascular inflammation.
METHODS: THP-1-derived macrophages, Sucnr1-deficient bone marrow-derived macrophages, and Apoe-/-/Sucnr1-/- mice were used to examine succinate/SUCNR1 signaling. Pharmacological inhibition, MYD88 overexpression, proteomics, qRT-PCR, Western blotting, co-immunoprecipitation, immunofluorescence, ELISA, and histology were performed.
RESULTS: SUCNR1 inhibition suppressed macrophage inflammatory signaling and reduced NLRP3 and IL-1β more prominently than NF-κB activation. Proteomics identified MYD88 as a downstream component. Succinate mainly increased MYD88 expression alone but strongly amplified inflammatory responses under low-dose LPS stimulation, indicating a priming effect. MYD88 overexpression restored NF-κB, NLRP3, and IL-1β responses and recovered MYD88-associated proximal signaling complexes during SUCNR1 inhibition. Mechanistically, succinate rapidly induced ERK phosphorylation, and ERK blockade reduced MYD88 mRNA and protein, placing ERK upstream of MYD88. In Apoe-/- mice, Sucnr1 deficiency attenuated plaque burden, lipid deposition, macrophage infiltration, and fibrotic remodeling, whereas MYD88 restoration partially reversed these protective effects.
CONCLUSION: Succinate/SUCNR1 signaling promotes atherosclerotic inflammation in part through ERK-dependent MYD88 upregulation, supporting SUCNR1 as a pharmacologically targetable node in immunometabolic vascular inflammation.