Abstract
Atrial fibrillation (AF) is more prevalent in patients with elevated interleukin (IL)-1β levels. Here we show that daily administration of IL-1β for 15 days sensitizes mice to AF, leading to fibrosis, accumulation of β-pleated sheet proteins in the left atrium, and systemic inflammation, resembling the pathophysiological changes observed in patients with AF. IL-1β administration creates a positive feedback loop, dependent on the IL-1 receptor (IL-1R) activity in cardiac resident macrophages. This results in increased caspase-1 maturation in the left atrium and elevated Il1b and Casp1 transcription in atrial macrophages. IL-1β treatment accelerated action potential and Ca2+ restitution in the left atrium, leading to action-potential shortening. This, along with increased caspase-1 maturation and IL-1R signaling, was essential for inducing AF. Lack of IL-1R in macrophages, but not cardiomyocytes, prevented IL-1β-induced AF sensitivity. By depleting recruited macrophages or deleting IL-1R specifically in cardiac resident macrophages, we further demonstrate that IL-1β/IL-1R signaling in these resident macrophages is responsible for increased AF susceptibility. These findings offer insights into the therapeutic potential of targeting IL-1β/IL-1R signaling in patients with AF and emphasize the importance of recognizing different underlying causes in this patient group.
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Data availability
RNA-seq data are available in the Gene Expression Omnibus (GEO) under accession number GEO: GSE284265. Source data are provided with this paper.
Code availability
Custom code for FTIR spectroscopy analysis is available via Zenodo at https://zenodo.org/record/7338651#.Y3vqYHZByUl (ref. 51). Custom code for HRV analysis is available via Zenodo at https://zenodo.org/record/7335949#.Y3f7PHZByUk (ref. 51).
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Acknowledgements
This work was funded by Carlos Chagas Filho Foundation for Supporting Research in the State of Rio de Janeiro (FAPERJ) E26/200.396/2020, 200.067/2024 (to O.M.-L.) and Fundação Maria Emilia (to O.M.-L.), and E. Medei receives personal grant PQ CNPq and grants E-26/210.155/2020, E-26/203.169/2017, E-26/210.191/2020, E-26/210.253/2020, E-203913/2024, E-210040/2023, CNPq 310681/2018-9, 308097/2022-0, and 406761/2022-1 INTERAS – INCT. F.F. receives personal grant 2R01HL 143450-05A1. We thank A. Mattiazzi of Centro de Investigaciones Cardiovasculares, Universidad Nacional de La Plata, for the critical discussion regarding the manuscript revision. We thank the FACS facility and Luminex facility from the Rede de Plataformas Tecnológicas Fiocruz. V.C.S. receives personal grant Program of Immunology and Inflammation, Federal University of Rio de Janeiro. P.T.B. receives personal grant FAPERJ E26/203.983/2024, E26/210.617/2023, and CNPq 442211/2024-4.
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E. Medei, A.L.E., P.T.B., C.N.P., R.M.-B., and O.M.-L. designed the experiments. O.M.-L., T.P.S., E. Medei, O.F.S., M.V.T.P., N.A.d.O.J., L.R.d.S., R.P.C., C.M.d.F., R.M.-B., J.C.P.S., J.d.R.F., A.S.d.S., D.A., and R.R.L. recruited participants for the study and collected clinical information and blood samples. O.M.-L., N.V.-N., A.R.d.Y.G., M.d.A.S., E. Medei, and A.L.E. performed and analyzed electrophysiology experiments. O.M.-L., N.V.-N., A.B.C.-J., T.P.S., E. Monteiro, T.H.K.-B., D.B.M., T.G.-S., T.M.C., F.M.d.S., and G.V.L.d.S. performed and analyzed FACS. V.C.S., S.S.G.D., L.M., H.M.-F., D.F.O., and B.C.B. performed western blots. O.M.-L., L.C., and M.J.C.-C. performed and analyzed mice multiplex assay. V.C.S., S.S.G.D., and P.T.B. performed and analyzed human multiplex assay. V.C.S., S.S.G.D., and P.T.B. performed cell culture and quantitative PCR from BMDM. O.M.-L. and J.P.d.V.M. analyzed RR series and HRV. M.d.A.S., T.P.S., A.B.P., L.P., E. Monteiro, M.C.A., and S.B.S. genotyped and performed experiments in Cre Lox mice. S.R.B. analyzed echocardiography exams. O.M.-L. and R.C.P. analyzed arrhythmias in mice after burst pacing. M.C.C., M.S.C.-R., and H.d.S.M. performed FTIR and SHG microscopy. O.M.-L., I.U., and F.F. recorded and analyzed optical mapping. O.M.-L., C.N.P., and E. Medei redacted the manuscript. All authors critically reviewed the manuscript and approved its final version.
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Extended data
Extended Data Fig. 1 Comparative mRNA expression in atrial samples of mice injected with saline or IL1β for 15 consecutives days.
a. Fold change was calculated dividing mean TPM values of IL1β -treated by the control group. Genes from the list of interest (n = 72) with absolute log2-fold change higher than 0.5 were displayed in red. The cumulative expression level of the genes is depicted in the x-axis as the sum of all the transcript per million of the four samples. b. Gene-set enrichment analysis interrogating KEGG data base. c. Gene-set enrichment analysis interrogating Reactome data base. d. Gene-set enrichment analysis interrogating Wikipathways data base. The top 10 up-regulated pathways are shown in blue and the top 10 down-regulated in orange (b-d).
Extended Data Fig. 2 IL-1β injection increases circulating neutrophils and macrophages.
a, Mice circulating biomarkers. b, Scheme of experimental design for leukocyte subsets in LA at 15 days post-injections. c, Mouse atria immune cells profile. All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. P values were calculated with Mann-Whitney’s test (two-tailed) (a), and unpaired Student’s t-test (two-tailed) (c).
Extended Data Fig. 3 Human circulating biomarkers.
Patients in sinus rhythm (SR) or in atrial fibrillation (AF) circulating biomarkers. All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. P values were calculated with Mann-Whitney’s test (two-tailed).
Extended Data Fig. 4 IL-1β injection does not produces maturation of IL-1β in left atria of Casp1-/-.
a, Serum levels of IL-6 in saline- and IL-1β–injected Casp1–/– mice. b, Western blot of IL-1β/pro-IL-1β in Casp1-/- mice. Quantitation levels were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) loading control. Each sample represents one mouse heart; 5 saline-injected and 6 IL-1β-injected, samples were analyzed. All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. P values were calculated with Mann-Whitney’s test (two-tailed) (a) and Student’s t-test (two-tailed) (b).
Extended Data Fig. 5 PKA and CaMKII expressions and the effect of Nifedipine on LA.
a, Western blot of Calcium-Calmodulin Kinase II δ (CaMKII), phospho-CaMKII Thr287 (p-CaMKII) and oxidized-CaMKII Met 281/282 (oxi-CAMKII). Quantitation levels were normalized to vinculin, used as loading control. Each sample represents one mouse heart; 5 saline-injected and 3 IL-1β-injected samples were analyzed. b Western blot of catalytic subunit of Protein kinase A (PKA). Quantitation levels were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) loading control. Each sample represents one mouse heart; 8 saline-injected and 8 IL-1β-injected samples were analyzed (see the second membrane in uncropped Material). c, APDs before and after Nifedipine perfusion (at 30%, 50%, 70%, and 90% of repolarization). Data are presented as individual values before and after condition. Data in a and b are presented as the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. Data in c is presented as individual values before and after condition. P values were calculated with unpaired Student’s t-test (two-tailed) (a,b), and paired samples Student’s t-test (two-tailed) (c).
Extended Data Fig. 6 Action Potential after 4-aminopyridine (4-AP) and atropine (Atrop) perfusion.
a, Graphical scheme of action potential recording after 15 min of 4-AP 2.5 mM perfusion. b, Representative traces of AP from saline and IL-1β groups perfused with Tyrode solution or 4-AP. c, Action potential duration (APD) at 30%, 50%, 70% and 90% of repolarization, from saline and IL-1β groups during perfusion with Tyrode (Tyr) or 4-AP. Data are presented as individual values before and after condition. d, Graphical scheme of action potential recording after 15 min of Atropine 10 µM perfusion. e, Representative traces of AP from saline and IL-1β groups perfused with Tyrode solution or atropine. f, APD at 30%, 50%, 70% and 90% of repolarization, from saline and IL-1β groups during perfusion with Tyrode (Tyr) or atropine (Atrop). Data are presented as individual values before and after condition. P values in c and f were calculated with paired samples Student’s t-test (two-tailed).
Extended Data Fig. 7 IL-1β injection increases arrhythmia susceptibility in a mechanism dependent of Casp1 expression and not IL-6.
a, graphical scheme of experiments. Casp1-/- mice were treated for 15 days with saline or IL-1β subcutaneously (SC). b, representative EKG traces from saline and IL-1β treated mice. c, EKG parameter analyzed: RR interval, p wave duration, and PR interval. d, representative action potential traces from saline and IL-1β treated Casp1-/- mice. e, action potential duration (APD) at 30%, 50%, 70% and 90% of repolarization, from saline and IL-1β treated mice. Lower inset panel show adjusted mean ± 95% C.I.f, triggered activities in Casp1-/- mice. g, graphical scheme of IL-6 restitution in Casp1-/- mice injected with IL-1β. h, representative EKG trace in sinus rhythm after burst-pacing in Casp1-/- mice injected with IL-1β and IL-6. i, AF inducibility after burst-pacing in Casp1-/- mice injected with IL-1β and IL-6. All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. Categorical data are presented as bar plots (f,i). P values were calculated with Student’s t-test (two-tailed) (c), hierarchical analysis with mixed effect model (e), and Fisher’s exact test (f,i) (two-tailed).
Extended Data Fig. 8 IL-1β injection increases arrhythmia susceptibility through activation of IL-1R.
a, graphical scheme of experiments. IL-1r-/- mice were treated for 15 days with saline or IL-1β subcutaneously (SC). b, representative EKG traces from saline and IL-1β treated mice. c, EKG parameters analyzed: RR interval, p wave duration, and PR interval. d, representative action potential traces from saline and IL-1β treated mice. e, action potential duration (APD) at 30%, 50%, 70% and 90% of repolarization, from saline and IL-1β treated mice. Lower inset panel show adjusted mean ± 95% C.I.All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. Categorical data are presented as bar plots (f). P values were calculated with unpaired Student’s t-test (two-tailed) (c), hierarchical analysis with mixed effect model (e), and Fisher’s exact test (two-tailed) (f).
Extended Data Fig. 9 IL-1β injection does not produces maturation of IL-1β in left atria of Csf1rCre IL-1rfl/fl.
a, graphical scheme of experiments. Csf1rCre IL-1rfl/fl mice were treated for 15 days with saline or IL-1β subcutaneously (SC). b, Western blot of IL-1β/pro-IL-1β in Csf1rCre IL-1rfl/fl mice. Quantitation levels were normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) loading control. Each sample represents one mouse heart; 5 saline-injected and 6 IL-1β-injected samples were analyzed. All the central lines in the box plots represent the median, the box limits represent the first and third quartiles and the whiskers denote the minimum and maximum values. P values were calculated with Student’s t-test.
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Moreno-Loaiza, O., Soares, V.C., de Assumpção Souza, M. et al. IL-1β enhances susceptibility to atrial fibrillation in mice by acting through resident macrophages and promoting caspase-1 expression. Nat Cardiovasc Res 4, 312–329 (2025). https://doi.org/10.1038/s44161-025-00610-8
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DOI: https://doi.org/10.1038/s44161-025-00610-8
