Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate–SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
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This study was supported by grants from the Spanish Ministry of Science, Innovation and Universities (PI14/00228 and PI17/01503 to J.V., SAF2015-65019-R to S.F.-V., SAF2014-56819-R and SAF2015-71878-REDT to A.C., BFU2016-78951-R to G.M.-M., PI15/00143 to C.S. and PI15/01562 to A.M., BFU2015-70454-REDT and BFU2017-90578-REDT to S.F.-V. and G.M.-M.) co-financed by the European Regional Development Fund (ERDF). The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. N.K. is recipient of a predoctoral fellowship from MINECO, Spain (FPI, BES-2016-077745). C.S. acknowledges support from the ‘Ramón y Cajal’ program from MINECO (RYC2013-13186) and S.F.-V. the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria, co-financed by the ERDF. We want to particularly acknowledge the patients and the BioBank IISPV (PT17/0015/0029) integrated in the Spanish National Biobanks Network for its collaboration. We also thank K. McCreath and A. Cervera for kindly providing the C57BL/6 Sucnr1fl/fl mice and for their helpful comments on the manuscript. Finally, we thank IRB Barcelona Functional Genomics Core Facility for Microarray processing and IRB Barcelona Biostatistics and Bioinformatics facility.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
a, Schematics showing from top to bottom, (1) the structure of the targeting vector including the loxP sites (red arrowheads) on either side of exon 2 of the Sucnr1 locus; (2) the locus after Flp-mediated recombination of the FRT sites (blue arrowheads); (3) the locus after Cre-mediated deletion of the loxP sites. Primers used for genotyping are shown by small arrows (Flp2 and flp3). Yellow boxes represent exons. b, Representative image of systematically mice genotyping; 300 bp band for wild-type (WT) allele; 450 bp band for loxP-containing (fl/fl) allele (left); and 700 bp band for the presence of Cre recombinase gene in mice (right).
Supplementary Figure 2 LysM-Cre Sucnr1fl/fl mice fed a NCD develop an inflammatory profile that precedes insulin resistance.
a, Fat weight of scWAT and vWAT from LysM-Cre Sucnr1fl/fl mice and age-matched control (Sucnr1fl/fl) littermates fed a NCD (n = 4 mice). b, Oxygen consumption (VO2), carbon dioxide (VCO2) production and energy expenditure (EE), for 3 d (n = 3). c, Food intake as in a from two independent experiments (n = 10 mice). d, GTT (left) and ITT (right) from top to bottom at 7 weeks (n = 6 mice for GTT and n = 5 for ITT), 12 weeks (n = 5 mice) and 15 weeks (n = 5 for Sucnr1fl/fl and n = 7 or 6 for GTT and ITT, respectively, for LysM-Cre Sucnr1fl/fl mice) of age. e, qPCR analysis of selected pro-inflammatory markers in scWAT and vWAT and liver from mice as in a (n = 4 mice). f, CD11b+ cells from total scWAT and vWAT SVF of mice as in a, expressed in percentages (n = 6 for Sucnr1fl/fl or 3 for LysM-Cre Sucnr1fl/fl biologically independent samples). g,h, Flow cytometry analyses of CD11b+/Ly6G+ population from SVF as in f (g, n = 3) biologically independent samples, positive cells are quantified and presented relative to the Sucnr1fl/fl group set as 1 and of CD11b+/CD11c+ and CD11b+/CD206+ population in SVF of scWAT as in f (h). Amounts of CD11c+, CD206+ or CD11c+CD206+ population are quantified and presented as relative percentage over the total number of cells analyzed (n = 3 biologically independent samples). All data are shown as mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed unpaired t-test in bar graphs and two-way ANOVA in GTT and ITT curves).
Supplementary Figure 3 The inflammatory profile associated with LysM-Cre Sucnr1fl/fl mice fed a HFD is accompanied by an increase in fat-depot mass and intracellular accumulation of succinate.
a–k, Male LysM-Cre Sucnr1fl/fl mice and age-matched Sucnr1fl/fl littermates were fed a HFD. a, Representative images of mouse size and scWAT depot content. b, Organ weight (n = 5 mice). c,d, Intracellular succinate levels in scWAT and vWAT (c, n = 4 mice except n = 5 for Sucnr1fl/fl scWAT) adipocytes (AD) (d, n = 4 for Sucnr1fl/fl and n = 3 or 7 for LysM-Cre Sucnr1fl/fl scWAT and vWAT, respectively) and ATMs (n = 6 or 7 for Sucnr1fl/fl scWAT and vWAT respectively and n = 3 for LysM-Cre Sucnr1fl/fl from biologically independent samples). e, Hematoxylin and eosin (H&E) staining of scWAT sections, representative images from two independent experiments (n = 4 mice). Scale bars 200 μm. f, Food intake from two independent experiments (n = 9 mice). g, VO2 consumption, VCO2 production for 4 d (n = 4 mice). h, Analysis of energy expenditure (EE) versus body weight of ANCOVA (n = 4 mice). i, GTT and ITT at 11 (left) or 15 weeks of age (right) (n = 5 mice except n = 7 for GTT at 15 weeks). j, VO2 consumption, VCO2 production and EE for a period of 24 h, before differences in body weight after 7 weeks on HFD (n = 5 mice). k, Flow cytometry analyses of CD11b+CD11c+ and CD11b+CD206+ population in SVF of scWAT. Amounts of CD11c+, CD206+ or CD11c+CD206+ are quantified and presented as relative percentage over the total number of cells analyzed, (n = 2 biologically independent samples). All data are shown as mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed unpaired t-test in bar graphs and two-way ANOVA in GTT and ITT curves).
Supplementary Figure 4 SUCNR1 is expressed predominantly in anti-inflammatory macrophages, and intra- and extracellular accumulation of succinate is associated with a pro-inflammatory phenotype.
a, Intracellular succinate levels in peritoneal macrophages from Sucnr1fl/fl mice without stimulation (ctrl) and stimulated with LPS or recombinant human IL-4 for 6 h (n = 3 biologically independent samples). (b) Succinate secretion in 24 h conditioned medium (left) (n = 4 biologically independent samples) and expression of SUCNR1 (right) (n = 5 biologically independent samples) in THP1 cells without stimulation (ctrl) and stimulated with LPS or recombinant human IL-4 for 6 h. c, qPCR analysis of expression of typical pro-inflammatory (left) and anti-inflammatory (right) markers from hPBMCs macrophages (BMI 22.87 ± 1.51) obtained by treatment with GM-CSF or M-CSF for 7 d (n = 4 biologically independent samples). d, qPCR analysis of expression of Sucnr1 in BMDMs unstimulated (ctrl) or stimulated with GM-CSF or M-CSF for 7 d (n = 3 biologically independent samples). e,f, Intracellular succinate levels in BMDMs stimulated with M-CSF for 7 d from Sucnr1fl/fl mice without treatment (ctrl) or stimulated with succinate (Succ) or dimethyl succinate (DS) for 1 h (g) and from Sucnr1fl/fl versuss LysM-Cre Sucnr1fl/fl mice (f) (n = 3 biologically independent samples). Values are expressed as mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed unpaired t-test).
a, Distribution of PU.1, H3K4me1, Stat6 and H3K27Ac tag densities in the vicinity of the Sucnr1 promoter in WT BMDMs untreated or treated for 2 h with IL-4. Data were obtained from GEO public database with accession number GSE38377 (left). Motif analysis obtained from IL-4 stimulation for 2 h, showing ChIP–seq dataset GSE72964, in which Stat6 peak was found in the promoter region, using web based MEME suite software (right). A motif logo representation (lower logo) as the best known motif matched, based on predictive P value was obtained using TOMTOM from MEME software suit (upper logo represents consensus sequence from JASPAR database). b,c, qPCR analysis in THP1 cells transfected with siRNAs against STAT6, KLF4 or ctrl and stimulated with human IL-4 for 6 h (b, n = 3 except for IL1RN n = 4 biologically independent samples) and in BMDMs stimulated with M-CSF followed by IL-4 stimulation for 6 h from Sucnr1fl/fl and Stat6−/− mice (c, n = 3 biologically independent samples). d, qPCR analysis from BMDMs as in c from Sucnr1fl/fl mice transfected as in b, before IL-4 treatment (n = 3 biologically independent samples). Results are presented relative to their respective basal state as 1 (without IL-4) for b–d. e,f, Representative images of immunoblot analysis and densitometric analysis in arbitrary units in BMDMs from Stat6−/− mice (e, n = 2 independent experiments) and in BMDMs stimulated with M-CSF from Sucnr1fl/fl mice (d, n = 3 independent experiments). Uncropped blots are provided in source data. Values are expressed as mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed unpaired t-test).
Supplementary Figure 6 Sucnr1 deficiency alters the transcriptional signature of ATMs in a depot-specific manner.
a,b, Heat map with GSEA normalized enrichment scores of gene expression profile for microarray of ATMs from LysM-Cre Sucnr1fl/fl and Sucnr1fl/fl mice from scWAT and vWAT in the pathway of interferon gamma, interferon alpha and inflammatory response (a) and TNF response and epithelial mesenchymal transition (b) gene sets from Hallmark. Data are from n = 4 biologically independent samples.
a,b, Microarrays analysis of scWAT and vWAT ATMs from LysM-Cre Sucnr1fl/fl and Sucnr1fl/fl mice. a, Log2(FC) in scWAT (x-axis) versus vWAT (y-axis) ATMs: top left quadrants (circles) are genes expressed higher in LysM-Cre Sucnr1fl/fl than in Sucnr1fl/fl for vWAT ATMs and lower in LysM-Cre Sucnr1fl/fl than in Sucnr1fl/fl for scWAT ATMs. Linear models with empirical Bayes statistic (Limma) were used for differential expression. Top right quadrants (diamonds) are genes expressed higher in LysM-Cre Sucnr1fl/fl than in Sucnr1fl/fl for both vWAT and scWAT ATMs. Bottom left quadrants (squares) are genes expressed lower in LysM-Cre Sucnr1fl/fl than in Sucnr1fl/fl for both vWAT and scWAT ATMs. Bottom right quadrants (triangles) are genes expressed lower in LysM-Cre Sucnr1fl/fl than in Sucnr fl/fl for vWAT and higher in LysM-Cre Sucnr1fl/fl than in Sucnr1fl/fl for scWAT ATMs. Non-yellow points correspond to genes with an |(log2(FC)| > log(2) and adjusted P < 0.05 in at least one of the two comparisons: orange and pink points distinguish between differentially expressed genes that go in the same direction (orange) for vWAT and scWAT ATMs and differentially expressed genes that go in opposite (pink) directions (signatures used in b for enrichment analysis), respectively. Differentially expressed genes for only scWAT ATMs and for only vWAT ATMs are represented in light and dark blue, respectively. Total number of genes in each of the groups is provided in the adjacent colored table. b, Hallmark gene set enrichment analysis for ATMs as in a using differentially expressed gene lists ‘scWAT LysM up & vWAT down’ (violet-triangle in a, shown in positive) and ‘scWAT LysM down & vWAT up’ (pink-circle in a, shown in negative), (hypergeometric test, Benjamini–Hochberg-adjusted P values, filtered by gene sets with P < 0.05). Data are from n = 4 biologically independent samples.
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Keiran, N., Ceperuelo-Mallafré, V., Calvo, E. et al. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat Immunol 20, 581–592 (2019). https://doi.org/10.1038/s41590-019-0372-7
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