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Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury

Nature Cardiovascular Research volume 4, pages 83–101 (2025)Cite this article

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Abstract

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species–dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.

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Fig. 1: AIF1 is increased in cardiac macrophages after acute MI in humans.
Fig. 2: AIF1 is increased in cardiac macrophages after MI in mice.
Fig. 3: Bone-marrow-derived AIF1 worsens cardiac repair after MI.
Fig. 4: Bone-marrow-derived AIF1 promotes inflammatory macrophage responses after MI.
Fig. 5: AIF1 promotes HIF-1α-dependent pro-inflammatory glycolytic reprogramming of macrophages after TLR4 stimulation.
Fig. 6: AIF1 interacts with RAC1 to promote pro-inflammatory glycolytic reprogramming of macrophages after TLR4 stimulation.
Fig. 7: AIF1-dependent pro-inflammatory glycolytic reprogramming of macrophages after TLR4 stimulation requires NOX activation.
Fig. 8: Therapeutic targeting of AIF1 with ASOs dampens inflammation and improves cardiac repair after MI.

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Data availability

Publicly available single-nuclei RNA sequencing data of human LV myocardium after acute MI were accessed at https://explore.data.humancellatlas.org/projects/e9f36305-d857-44a3-93f0-df4e6007dc97. Publicly available single-cell RNA sequencing data of mouse hearts after acute MI were accessed at https://infection-atlas.org/Rizzo2022/. All other data generated in this study are provided in the Source Data and Supplementary Information sections.

Code availability

The code used to analyze the single-nuclei RNA sequencing dataset is available on GitHub at https://github.com/thorplab.

References

  1. Tsao, C. W. et al. Heart Disease and Stroke Statistics—2022 Update: a report from the American Heart Association. Circulation 145, e153–e639 (2022).

    PubMed  Google Scholar 

  2. Guillen, I., Blanes, M., Gomez-Lechon, M. J. & Castell, J. V. Cytokine signaling during myocardial infarction: sequential appearance of IL-1 beta and IL-6. Am. J. Physiol. 269, R229–R235 (1995).

    CAS  PubMed  Google Scholar 

  3. Gabriel, A. S., Martinsson, A., Wretlind, B. & Ahnve, S. IL-6 levels in acute and post myocardial infarction: their relation to CRP levels, infarction size, left ventricular systolic function, and heart failure. Eur. J. Intern. Med. 15, 523–528 (2004).

    CAS  PubMed  Google Scholar 

  4. Ridker, P. M. et al. Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation 101, 2149–2153 (2000).

    CAS  PubMed  Google Scholar 

  5. Huang, S. & Frangogiannis, N. G. Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. Br. J. Pharmacol. 175, 1377–1400 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019).

  7. Faxon, D. P., Gibbons, R. J., Chronos, N. A. F., Gurbel, P. A. & Sheehan, F. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J. Am. Coll. Cardiol. 40, 1199–1204 (2002).

    CAS  PubMed  Google Scholar 

  8. Thorp, E. B. Cardiac macrophages and emerging roles for their metabolism after myocardial infarction. J. Clin. Invest. 133, e171953 (2023).

  9. DeBerge, M., Chaudhary, R., Schroth, S. & Thorp, E. B. Immunometabolism at the heart of cardiovascular disease. JACC Basic Transl. Sci. 8, 884–904 (2023).

    PubMed  PubMed Central  Google Scholar 

  10. Koelwyn, G. J., Corr, E. M., Erbay, E. & Moore, K. J. Regulation of macrophage immunometabolism in atherosclerosis. Nat. Immunol. 19, 526–537 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, S. et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, 443–456 (2019).

    CAS  PubMed  Google Scholar 

  12. DeBerge, M. et al. Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair. J. Exp. Med. 218, e20200667 (2021).

  13. Kido, M. et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J. Am. Coll. Cardiol. 46, 2116–2124 (2005).

    CAS  PubMed  Google Scholar 

  14. Rowley, A. H. et al. Allograft inflammatory factor-1 links T-cell activation, interferon response, and macrophage activation in chronic Kawasaki disease arteritis. J. Pediatric Infect. Dis. Soc. 6, e94–e102 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Chen, Z.-W. et al. Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats. Proc. Natl Acad. Sci. USA 94, 13879–13884 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schluesener, H. J., Seid, K., Kretzschmar, J. & Meyermann, R. Allograft-inflammatory factor-1 in rat experimental autoimmune encephalomyelitis, neuritis, and uveitis: expression by activated macrophages and microglial cells. Glia 24, 244–251 (1998).

    CAS  PubMed  Google Scholar 

  17. Utans, U., Arceci, R. J., Yamashita, Y. & Russell, M. E. Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection. J. Clin. Invest. 95, 2954–2962 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, Y. et al. Upregulation of allograft inflammatory factor‑1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype. Int. J. Mol. Med. 42, 861–872 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Harney, S. M. J. et al. Fine mapping of the MHC class III region demonstrates association of AIF1 and rheumatoid arthritis. Rheumatology 47, 1761–1767 (2008).

    CAS  PubMed  Google Scholar 

  20. Mishima, T. et al. Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice. Int. J. Mol. Med. 21, 181–187 (2008).

    CAS  PubMed  Google Scholar 

  21. Postler, E., Rimner, A., Beschorner, R., Schluesener, H. J. & Meyermann, R. Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions. J. Neuroimmunol. 104, 85–91 (2000).

    CAS  PubMed  Google Scholar 

  22. Kuppe, C. et al. Spatial multi-omic map of human myocardial infarction. Nature 608, 766–777 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lavine, K. J. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. USA 111, 16029–16034 (2014).

  24. Rizzo, G. et al. Dynamics of monocyte-derived macrophage diversity in experimental myocardial infarction. Cardiovasc. Res. 127, e232–e249 (2022).

  25. Autieri, M. V. et al. Allograft inflammatory factor-1 expression correlates with cardiac rejection and development of cardiac allograft vasculopathy. Circulation 106, 2218–2223 (2002).

    CAS  PubMed  Google Scholar 

  26. Kelemen, S. E. & Autieri, M. V. Expression of allograft inflammatory factor-1 in T lymphocytes: a role in T-lymphocyte activation and proliferative arteriopathies. Am. J. Pathol. 167, 619–626 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lindsey, M. L. et al. Reperfused vs. nonreperfused myocardial infarction: when to use which model. Am. J. Physiol. Heart Circ. Physiol. 321, H208–H213 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Elizondo, D. M., Brandy, N. Z. D., da Silva, R. L., de Moura, T. R. & Lipscomb, M. W. Allograft inflammatory factor-1 in myeloid cells drives autoimmunity in type 1 diabetes. JCI Insight 5, e136092 (2020).

  29. Heng, T. S. P. et al. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    CAS  PubMed  Google Scholar 

  30. Egaña-Gorroño, L. et al. Allograft inflammatory factor-1 supports macrophage survival and efferocytosis and limits necrosis in atherosclerotic plaques. Atherosclerosis 289, 184–194 (2019).

    PubMed  PubMed Central  Google Scholar 

  31. Heidt, T. et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ. Res. 115, 284–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Jiang, W. et al. Necrotic cardiac myocytes skew macrophage polarization towards a classically activated phenotype. PLoS ONE 18, e0282921 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hayashi, T. et al. The programmed death-1 signaling axis modulates inflammation and LV structure/function in a stress-induced cardiomyopathy model. JACC Basic Transl. Sci. 7, 1120–1139 (2022).

    PubMed  PubMed Central  Google Scholar 

  34. Zhang, W. et al. Necrotic myocardial cells release damage‐associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J. Am. Heart Assoc. 4, e001993 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

  36. Autieri, M. V. & Chen, X. The ability of AIF-1 to activate human vascular smooth muscle cells is lost by mutations in the EF-hand calcium-binding region. Exp. Cell Res. 307, 204–211 (2005).

    CAS  PubMed  Google Scholar 

  37. Brown, D. M. et al. Calcium and ROS-mediated activation of transcription factors and TNF-α cytokine gene expression in macrophages exposed to ultrafine particles. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L344–L353 (2004).

    CAS  PubMed  Google Scholar 

  38. Schappe, M. S. et al. Chanzyme TRPM7 mediates the Ca2+ influx essential for lipopolysaccharide-induced Toll-like receptor 4 endocytosis and macrophage activation. Immunity 48, 59–74 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Autieri, M. V., Kelemen, S. E. & Wendt, K. W. AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration. Circ. Res. 92, 1107–1114 (2003).

    CAS  PubMed  Google Scholar 

  40. Price, L. S. et al. Calcium signaling regulates translocation and activation of Rac. J. Biol. Chem. 278, 39413–39421 (2003).

    CAS  PubMed  Google Scholar 

  41. Wheeler, A. P. et al. Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. J. Cell Sci. 119, 2749–2757 (2006).

    CAS  PubMed  Google Scholar 

  42. Geng, J. et al. TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection. Nat. Commun. 12, 3519 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bosco, E. E., Mulloy, J. C. & Zheng, Y. Rac1 GTPase: a ‘Rac’ of all trades. Cell. Mol. Life Sci. 66, 370 (2008).

    PubMed Central  Google Scholar 

  44. Hirota, K. & Semenza, G. L. Rac1 activity is required for the activation of hypoxia-inducible factor 1. J. Biol. Chem. 276, 21166–21172 (2001).

    CAS  PubMed  Google Scholar 

  45. Sumbayev, V. V. LPS-induced Toll-like receptor 4 signalling triggers cross-talk of apoptosis signal-regulating kinase 1 (ASK1) and HIF-1α protein. FEBS Lett. 582, 319–326 (2008).

    CAS  PubMed  Google Scholar 

  46. Zimmerman, M. C. et al. Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ. Res. 95, 532–539 (2004).

    CAS  PubMed  Google Scholar 

  47. Bouin, A.-P., Grandvaux, N., Vignais, P. V. & Fuchs, A. p40phox is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase: implication of a protein kinase C-type kinase in the phosphorylation process. J. Biol. Chem. 273, 30097–30103 (1998).

    CAS  PubMed  Google Scholar 

  48. Piotrowska, K. et al. Over-expression of allograft inflammatory factor-1 (AIF-1) in patients with rheumatoid arthritis. Biomolecules 10, 1064 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Dick Sarah, A. & Epelman, S. Chronic heart failure and inflammation. Circ. Res. 119, 159–176 (2016).

    CAS  PubMed  Google Scholar 

  50. Yang, Z. F. et al. Allograft inflammatory factor-1 (AIF-1) is crucial for the survival and pro-inflammatory activity of macrophages. Int. Immunol. 17, 1391–1397 (2005).

    CAS  PubMed  Google Scholar 

  51. Li, Q. et al. Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nat. Commun. 11, 1456 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Baillet, A. et al. Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase. FASEB J. 31, 663–673 (2017).

    CAS  PubMed  Google Scholar 

  53. Yuan, X. et al. Aldosterone promotes renal interstitial fibrosis via the AIF‑1/AKT/mTOR signaling pathway. Mol. Med. Rep. 20, 4033–4044 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Knoops, B. et al. Specific interactions measured by AFM on living cells between peroxiredoxin-5 and TLR4: relevance for mechanisms of innate immunity. Cell Chem. Biol. 25, 550–559 (2018).

    CAS  PubMed  Google Scholar 

  55. Bolognese, L. & Cerisano, G. Early predictors of left ventricular remodeling after acute myocardial infarction. Am. Heart J. 138, S79–S83 (1999).

    CAS  PubMed  Google Scholar 

  56. Frangogiannis, N. G. Matricellular proteins in cardiac adaptation and disease. Physiol. Rev. 92, 635–688 (2012).

    CAS  PubMed  Google Scholar 

  57. Park, J. S. et al. Mechanical regulation of glycolysis via cytoskeleton architecture. Nature 578, 621–626 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Previtera, M. L. & Sengupta, A. Substrate stiffness regulates proinflammatory mediator production through TLR4 activity in macrophages. PLoS ONE 10, e0145813 (2016).

    Google Scholar 

  59. Dehn, S. & Thorp, E. B. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair. FASEB J. 32, 254–264 (2018).

    CAS  PubMed  Google Scholar 

  60. De Zoysa, M. et al. Allograft inflammatory factor-1 in disk abalone (Haliotis discus discus): molecular cloning, transcriptional regulation against immune challenge and tissue injury. Fish Shellfish Immunol. 29, 319–326 (2010).

    PubMed  Google Scholar 

  61. Chiaramonte, M. et al. Allograft inflammatory factor AIF-1: early immune response in the Mediterranean sea urchin Paracentrotus lividus. Zoology 142, 125815 (2020).

    PubMed  Google Scholar 

  62. da Silva, R. L. et al. Leishmania donovani infection suppresses allograft inflammatory factor-1 in monocytes and macrophages to inhibit inflammatory responses. Sci. Rep. 11, 946 (2021).

    PubMed  PubMed Central  Google Scholar 

  63. Lai, Y., Wang, Y., Fan, X. & Zhao, Y. Allograft inflammatory factor-1 stimulates inflammatory properties of peripheral blood leukocytes and increases cell viability via enhancing mitochondrial function in Ctenopharyngodon idellus. Fish Shellfish Immunol. 127, 412–418 (2022).

    CAS  PubMed  Google Scholar 

  64. Rohde, D. et al. S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4. EMBO Mol. Med. 6, 778–794 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Timmers, L. et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ. Res. 102, 257–264 (2008).

    CAS  PubMed  Google Scholar 

  66. Olsen, A.-M. S. et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction. Circulation 123, 2226–2235 (2011).

    Google Scholar 

  67. Abbate, A. et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am. J. Cardiol. 111, 1394–1400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Broch, K. et al. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 77, 1845–1855 (2021).

    CAS  PubMed  Google Scholar 

  69. Yi, S. et al. Surface engineered polymersomes for enhanced modulation of dendritic cells during cardiovascular immunotherapy. Adv. Funct. Mater. 29, 1904399 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang, X. et al. CC chemokine receptor 2-targeting copper nanoparticles for positron emission tomography-guided delivery of gemcitabine for pancreatic ductal adenocarcinoma. ACS Nano 15, 1186–1198 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. van der Laan, A. M. et al. Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir. Eur. Heart J. 35, 376–385 (2013).

    PubMed  PubMed Central  Google Scholar 

  72. Casimiro, I., Chinnasamy, P. & Sibinga, N. E. S. Genetic inactivation of the allograft inflammatory factor-1 locus. Genesis 51, 734–740 (2013).

    CAS  PubMed  Google Scholar 

  73. Wan, E. et al. Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction. Circ. Res. 113, 1004–1012 (2013).

    CAS  PubMed  Google Scholar 

  74. Crooke, S. T., Witztum, J. L., Bennett, C. F. & Baker, B. F. RNA-targeted therapeutics. Cell Metab. 27, 714–739 (2018).

    CAS  PubMed  Google Scholar 

  75. Shen, W. et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat. Biotechnol. 37, 640–650 (2019).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the American Heart Association (grant CDA34110032 to M.D.) and the National Institutes of Health (grants R01HL122309 to E.B.T. and R01HL163635 to N.S.). These studies used sequencing services provided by the NUSeq Core and imaging services provided by the Center for Advanced Microscopy & Nikon Imaging Center at Northwestern University. Figure schematics were created with Servier Medical Art and BioRender. Copies of the licenses to use these programs are provided in Supplementary Table 8. Publication costs for this research were also supported by the Sidney & Bess Eisenberg Memorial Fund.

Author information

Author notes

  1. These authors contributed equally: Matthew DeBerge, Kristofor Glinton.

Authors and Affiliations

  1. Department of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas Health Science Center, Houston, TX, USA

    Matthew DeBerge, Swapna Patil & Bo Ryung Lee

  2. Department of Pathology, Northwestern University, Chicago, IL, USA

    Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P. Sullivan, Minori I. Thorp, Shuling Han & Edward B. Thorp

  3. Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA

    Adam Mullick & Steve Yeh

  4. Department of Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Anja M. van der Laan

  5. Department of Pathology and Cardiac Surgery, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU Medical Center, Amsterdam, The Netherlands

    Hans W. M. Niessen

  6. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Xunrong Luo

  7. Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA

    Nicholas E. S. Sibinga

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Contributions

M.D., K.G. and E.B.T. designed the research studies. M.D., K.G., D.P.S., S.P., B.R.L., M.I.T., X.L., N.E.S.S. and E.B.T. performed and analyzed experiments. C.L. analyzed single-nuclei RNA sequencing data. Z.-D.G. and S.H. performed echocardiography. A.M.v.d.L. and H.W.M.N. collected and provided human specimens. A.M. and S.Y. prepared and characterized ASOs. N.E.S.S. provided Aif1-deficient mice. M.D. and E.B.T. wrote the manuscript, and all authors contributed to manuscript revision.

Corresponding authors

Correspondence to Matthew DeBerge or Edward B. Thorp.

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Nature Cardiovascular Research thanks Benjamin L. Prosser, Rong Tian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Allograft inflammatory factor 1 (Aif1) is enriched within recruited inflammatory macrophage clusters, but not lymphocytes, after myocardial infarction (MI) in mice.

A Using the Infection Atlas (Rizzo 2022) to visualize publicly available single cell RNA sequencing data (GSE135310, GSE197441, GSE197853), Aif1 expression was analyzed among monocytes and macrophages isolated from the hearts of mice at various time points after MI. Inflammatory myeloid subsets include Ly6Chi monocytes (Ly6Chi mo) and recruited macrophage clusters (Res MHCII, MHCII + IL1B + , and Isg15). B Aif1 gene expression in cardiac T and B cells 5 days after MI as visualized using the Infection Atlas. C AIF1 expression in peripheral blood lymphocytes 5 days after MI. Dashed lines represent fluorescence minus one (FMO) staining controls (n = 4 naïve and n = 4 day 5 MI, two-tailed unpaired t test, pooled from two independent experiments). Data are presented as mean ± SEM.

Source data

Extended Data Fig. 2 Allograft inflammatory factor 1 (Aif1) worsens cardiac repair after myocardial infarction (MI).

A Mice with whole body deletion of Aif1 (Aif1-/-) or controls (Aif1 + /+) were subjected to permanent occlusion MI. Percent infarct (INF)/left ventricle (LV), percent area-at-risk (AAR)/LV, and percent INF/AAR were measured one week after MI (n = 5 Aif1 + /+ and n = 6 Aif1-/-, two-tailed unpaired t test, pooled from two independent experiments). B Gene expression in whole cardiac extracts from Aif1 + /+ or Aif1-/- bone marrow chimera mice (n = 3 naïve and n = 5 day 3 MI, two-way ANOVA with Tukey’s test, pooled from two independent experiments). Data are presented as mean ± SEM.

Source data

Extended Data Fig. 3 Allograft inflammatory factor 1 (AIF1) in macrophages promotes glycolytic metabolism and inflammatory activation in response to necrotic myocardial cells but is dispensable for macrophage efferocytosis and efferocytic production of IL-10.

A Gene expression in bone marrow-derived macrophages (BMDM) after treatment with necrotic myocardial cell (NMC) extracts or lipopolysaccharide (LPS) (n = 4 untreated, n = 3 NMC or LPS, two-way ANOVA with Tukey’s test, two independent experiments). B Extracellular acidification rate (ECAR) in BMDMs after treatment with NMC extracts (n = 6 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). C Percent efferocytosis of apoptotic Jurkat cells co-cultured with BMDMs. Scale bar, 10μm. D IL-10 production by efferocytic BMDMs (for C and D, n = 4 for all groups, two-tailed unpaired t test, two independent experiments). Data are presented as mean ± SEM.

Source data

Extended Data Fig. 4 Allograft inflammatory factor 1 (AIF1) promotes Hypoxia Inducible Factor (HIF)-1α-dependent glycolysis after myocardial infarction (MI).

A HIF-1α activation in cardiac macrophages 3 days after MI (n = 3 day 0 MI and n = 6 day 3 MI, two-way ANOVA with Tukey’s test, pooled from two independent experiments). B Isolation of cardiac macrophages 3 days after MI with representative enrichment assessed by flow cytometry. C Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) by cardiac macrophages isolated from the infarct 3 days after MI (n = 4 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). D Publicly available microarray data (GSE112630) of cytokine and glycolytic gene expression among CCR2+ and CCR2− macrophages isolated from the hearts of patients during ischemic (ICM) or dilated cardiomyopathy (DCM). Data are presented as mean ± SEM.

Source data

Extended Data Fig. 5 Calcium influx is required for inflammatory glycolytic reprogramming of macrophages after TLR4 stimulation.

A Calcium influx in bone marrow-derived macrophages (BMDM) after TLR4 or ionomycin (IM) stimulation. Images are representative of two independent experiments. Scale bar, 20 μm. B Cytokine production by BMDMs treated with a cell-permeable, calcium chelator (BAPTA) (n = 4 for IL-6 and TNF-α and n = 3 for IL-10, two-way ANOVA with Tukey’s test, three independent experiments). Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in BMDMs after treatment with calcium chelators, C BAPTA or D EGTA. Vehicle treated groups are the same in C and D (n = 6 vehicle and n = 8 for all other groups, two-way ANOVA with Tukey’s test, two independent experiments). E ECAR and OCR in BMDMs treated with ionomycin (n = 5 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). Data are presented as mean ± SEM.

Source data

Extended Data Fig. 6 Allograft inflammatory factor 1 (AIF1) is dispensable for calcium influx in macrophages after TLR4 stimulation.

A Mean fluorescent intensity (MFI) of the calcium indicator dye, Fluo-4, in bone marrow-derived macrophages (BMDM) 30 minutes after TLR4 stimulation as measured by fluorescent microscopy. Scale bar, 10μm (n = 10 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). B Kinetics of Fluo-4 MFI in BMDMs after TLR4 stimulation as measured by a fluorescent plate reader (n = 3 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). Data are presented as mean ± SEM.

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Extended Data Fig. 7 Actin polymerization is required for inflammatory glycolytic reprogramming of macrophages after TLR4 stimulation.

A Rac1 knockdown efficiency in bone marrow-derived macrophages (BMDM) (n = 4 for all groups, two-tailed unpaired t test, two independent experiments. B Cytokine production by BMDMs treated with a cell-permeable, actin polymerization inhibitor, Cytochalasin D (CytoD) (n = 4 for all groups, two-way ANOVA with Tukey’s test, three independent experiments). C Extracellular acidification rate (ECAR) in BMDMs after treatment with CytoD (n = 3 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). D Actin polymerization in cardiac macrophages 3 days after MI (n = 3 day 0 MI and n = 6 day 3 MI, two-way ANOVA with Tukey’s test, pooled from two independent experiments). Data presented as mean ± SEM.

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Extended Data Fig. 8 Role of Hypoxia inducible factor 1 (HIF)-1α in Rac1 activation, membrane ruffling, glycolysis, and transcription after TLR4 stimulation.

A Rac1-GTP levels in bone marrow derived macrophages (BMDMs) after 1 hour of TLR4 stimulation with lipopolysaccharide (LPS). Dashed line represents background absorbance level (n = 4 for all groups, two-way ANOVA with Tukey’s test, two independent experiments). B F-actin immunostaining of BMDMs after 1 hour of TLR4 stimulation with quantification of membrane ruffling area (μm2) (n = 30 for all groups, whiskers 10-90 percentile, two-way ANOVA with Tukey’s test, two independent experiments). C Extracellular acidification rate (ECAR) in BMDMs after TLR4 stimulation with LPS (n = 12 vehicle and n = 16 LPS, two-way ANOVA with Tukey’s test, two independent experiments). D ECAR of Hif1 + /+ and Hif1-/- BMDMs after TLR4 stimulation (n = 14 unstimulated and n = 16 LPS, two-way ANOVA with Tukey’s test, two independent experiments). E Gene expression in BMDMs after TLR4 stimulation (n = 4 for all groups, one-way ANOVA with Dunnett’s test, two independent experiments). F Gene expression in Hif1 + /+ and Hif1-/- BMDMs after 3 hours of TLR4 stimulation (n = 3 unstimulated and n = 4 LPS, two-way ANOVA with Tukey’s test, two independent experiments). Data presented as mean ± SEM.

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Extended Data Fig. 9 Allograft inflammatory factor 1 (Aif1) antisense oligonucleotide (ASO) dose response.

ASOs were formulated in PBS, administered at doses of 1.6, 8, 40, and 75 mg/kg, and injected subcutaneously on days 0, 6, and 10. Aif1 tissue expression and general ASO tolerability was evaluated on day 14. Gene expression levels of Aif1 in A heart and B liver. Gene expression levels of Ccl2 in C heart and D liver. E Liver or F spleen weight as a percent of total body weight. Plasma levels of G alanine transaminase or H creatinine (n = 6 PBS, n = 3 for 1.6, 8, and 40 mg/kg, and n = 2 for 75 mg/kg, one-way ANOVA with Dunnett’s test, pooled from two independent experiments). Data presented as mean ± SEM.

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Extended Data Fig. 10 Mechanical regulation of macrophage metabolism by Allograft Inflammatory Factor 1 (AIF1) leads to adverse remodeling after cardiac injury.

Myocardial infarction leads to necrotic death of cardiomyocytes and release of damage associated molecular patterns (DAMPs). Recognition of DAMPs on macrophages by Toll-like Receptors (TLR), including TLR4, leads to calcium influx and activation of Allograft Inflammatory Factor 1 (AIF1). AIF1 interacts with RAC1 to promote actin polymerization and mechanical stiffness. This activates NADPH oxidase (NOX) and increases reactive oxygen species (ROS) production. Elevated ROS levels stabilize Hypoxia Inducible Factor (HIF)-1α, leading to its nuclear translocation and transcription of genes involved in glycolysis and inflammation. This switch to glycolytic metabolism fuels increased production of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which contribute to adverse left ventricular remodeling and progression to heart failure (HF).

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Supplementary Tables 1–8. Lists of antibodies, chemicals, peptides and recombinant proteins, commercial assays, cell lines, mouse strains, qPCR primers, recombinant DNA and software.

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DeBerge, M., Glinton, K., Lantz, C. et al. Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury. Nat Cardiovasc Res 4, 83–101 (2025). https://doi.org/10.1038/s44161-024-00585-y

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