Skip to main content
SpringerLink
Log in

Splenic monocytes mediate inflammatory response and exacerbate myocardial ischemia/reperfusion injury in a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) recruits inflammasomes, initiating inflammatory responses and mediating tissue injury. We hypothesize that myocardial cell-free DNA (cfDNA) activates the splenic NLRP3 inflammasome during early reperfusion, increases systemic inflammatory response, and exacerbates myocardial infarct. Mice were subjected to 40 min of ischemia followed by 0, 1, 5, or 15 min, or 24 h of reperfusion. Splenic leukocyte adoptive transfer was performed by injecting isolated splenocytes to mice with splenectomy performed prior to left coronary artery occlusion. CY-09 (4 mg/kg) was administered 5 min before reperfusion. During post-ischemic reperfusion, splenic protein levels of NLRP3, cleaved caspase-1, and interleukin-1β (IL-1β) were significantly elevated and peaked (2.1 ± 0.2-, 3.4 ± 0.4-, and 3.2 ± 0.2-fold increase respectively, p < 0.05) within 5 min of reperfusion. In myocardial tissue, NLRP3 was not upregulated until 24 h after reperfusion. Suppression by CY09, a specific NLRP3 inflammasome inhibitor, or deficiency of NLRP3 significantly reduced myocardial infarct size (17.3% ± 4.2% and 33.2% ± 1.8% decrease respectively, p < 0.01). Adoptive transfer of NLRP3−/− splenocytes to WT mice significantly decreased infarct size compared to transfer of WT splenocytes (19.1% ± 2.8% decrease, p < 0.0001). NLRP3 was mainly activated at 5 min after reperfusion in CD11b+ and LY6G− splenocytes, which significantly increased during reperfusion (24.8% ± 0.7% vs.14.3% ± 0.6%, p < 0.0001). The circulating cfDNA level significantly increased in patients undergoing cardiopulmonary bypass (CPB) (43.3 ± 5.3 ng/mL, compared to pre-CPB 23.8 ± 3.5 ng/mL, p < 0.01). Mitochondrial cfDNA (mt-cfDNA) contributed to NLRP3 activation in macrophages (2.1 ± 0.2-fold increase, p < 0.01), which was inhibited by a Toll-like receptor 9(TLR9) inhibitor. The NLRP3 inflammasome in splenic monocytes is activated and mediates the inflammatory response shortly after reperfusion onset, exacerbating MI/R injury in mt-cfDNA/TLR9-dependent fashion.

Graphical abstract

The schema reveals splenic NLRP3 mediates the inflammatory response in macrophages and exacerbates MI/R in a mitochondrial cfDNA/ TLR9-dependent fashion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Materials, experiment procedures, data collection protocols, and analytic methods will be made available to other researchers as requested for purposes of experiment reproduction, procedural replication, and for collaborative study. The data supporting the findings of this study are available within the article and its supplementary material. Raw data that support the findings of this study are available from the corresponding author, upon reasonable request.

References

  1. Andreadou I, Cabrera-Fuentes HA, Devaux Y, Frangogiannis NG, Frantz S, Guzik T, Liehn EA, Gomes CPC, Schulz R, Hausenloy DJ (2019) Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities. Cardiovasc Res 115:1117–1130. https://doi.org/10.1093/cvr/cvz050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, Chang B, Duramad O, Coffman RL (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202:1131–1139. https://doi.org/10.1084/jem.20050914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bliksoen M, Mariero LH, Torp MK, Baysa A, Ytrehus K, Haugen F, Seljeflot I, Vaage J, Valen G, Stenslokken KO (2016) Extracellular mtDNA activates NF-kappaB via toll-like receptor 9 and induces cell death in cardiomyocytes. Basic Res Cardiol 111:42. https://doi.org/10.1007/s00395-016-0553-6

    Article  CAS  PubMed  Google Scholar 

  4. Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. den Haan JM, Kraal G (2012) Innate immune functions of macrophage subpopulations in the spleen. J Innate Immun 4:437–445. https://doi.org/10.1159/000335216

    Article  Google Scholar 

  6. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329. https://doi.org/10.1038/nature11260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Eltzschig HK, Eckle T (2011) Ischemia and reperfusion–from mechanism to translation. Nat Med 17:1391–1401. https://doi.org/10.1038/nm.2507

    Article  CAS  PubMed  Google Scholar 

  8. Emami H, Singh P, MacNabb M, Vucic E, Lavender Z, Rudd JH, Fayad ZA, Lehrer-Graiwer J, Korsgren M, Figueroa AL, Fredrickson J, Rubin B, Hoffmann U, Truong QA, Min JK, Baruch A, Nasir K, Nahrendorf M, Tawakol A (2015) Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc Imaging 8:121–130. https://doi.org/10.1016/j.jcmg.2014.10.009

    Article  PubMed  PubMed Central  Google Scholar 

  9. Evavold CL, Ruan J, Tan Y, Xia S, Wu H, Kagan JC (2018) The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity 48(35–44):e36. https://doi.org/10.1016/j.immuni.2017.11.013

    Article  CAS  Google Scholar 

  10. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES (2007) The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ 14:1590–1604. https://doi.org/10.1038/sj.cdd.4402194

    Article  CAS  PubMed  Google Scholar 

  11. Franchi L, Warner N, Viani K, Nunez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227:106–128. https://doi.org/10.1111/j.1600-065X.2008.00734.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frank MG, Weber MD, Fonken LK, Hershman SA, Watkins LR, Maier SF (2016) The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome. Brain Behav Immun 55:215–224. https://doi.org/10.1016/j.bbi.2015.10.009

    Article  CAS  PubMed  Google Scholar 

  13. Garcia-Dorado D, Theroux P, Elizaga J, Galinanes M, Solares J, Riesgo M, Gomez MJ, Garcia-Dorado A, Fernandez Aviles F (1987) Myocardial reperfusion in the pig heart model: infarct size and duration of coronary occlusion. Cardiovasc Res 21:537–544. https://doi.org/10.1093/cvr/21.7.537

    Article  CAS  PubMed  Google Scholar 

  14. Glogar DH (1986) Definition and significance of the area at risk in myocardial infarct and the ischemic border zone in acute myocardial infarct. Acta Med Austriaca Suppl 36:1–40

    CAS  PubMed  Google Scholar 

  15. Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687. https://doi.org/10.1038/nm.3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Haneklaus M, O’Neill LA (2015) NLRP3 at the interface of metabolism and inflammation. Immunol Rev 265:53–62. https://doi.org/10.1111/imr.12285

    Article  CAS  PubMed  Google Scholar 

  17. Heusch G (2023) Cardioprotection and its Translation: A Need for New Paradigms? Or for New Pragmatism? An Opinionated Retro- and Perspective. J Cardiovasc Pharmacol Ther 28:10742484231179612. https://doi.org/10.1177/10742484231179613

    Article  PubMed  Google Scholar 

  18. Heusch G (2017) Critical Issues for the Translation of Cardioprotection. Circ Res 120:1477–1486. https://doi.org/10.1161/CIRCRESAHA.117.310820

    Article  CAS  PubMed  Google Scholar 

  19. Heusch G (2020) Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 17:773–789. https://doi.org/10.1038/s41569-020-0403-y

    Article  PubMed  Google Scholar 

  20. Heusch G (2019) The Spleen in Myocardial Infarction. Circ Res 124:26–28. https://doi.org/10.1161/CIRCRESAHA.118.314331

    Article  CAS  PubMed  Google Scholar 

  21. Hiraiwa H, Okumura T, Murohara T (2022) The cardiosplenic axis: the prognostic role of the spleen in heart failure. Heart Fail Rev 27:2005–2015. https://doi.org/10.1007/s10741-022-10248-4

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ismahil MA, Hamid T, Bansal SS, Patel B, Kingery JR, Prabhu SD (2014) Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res 114:266–282. https://doi.org/10.1161/CIRCRESAHA.113.301720

    Article  CAS  PubMed  Google Scholar 

  23. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q, Jin T, Jiang W, Deng X, Zhou R (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med 214:3219–3238. https://doi.org/10.1084/jem.20171419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123:594–604. https://doi.org/10.1161/CIRCULATIONAHA.110.982777

    Article  CAS  PubMed  Google Scholar 

  25. Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289. https://doi.org/10.1038/nri2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kubota A, Frangogiannis NG (2022) Macrophages in myocardial infarction. Am J Physiol Cell Physiol 323:C1304–C1324. https://doi.org/10.1152/ajpcell.00230.2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Leemans JC, Cassel SL, Sutterwala FS (2011) Sensing damage by the NLRP3 inflammasome. Immunol Rev 243:152–162. https://doi.org/10.1111/j.1600-065X.2011.01043.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li L, Ni L, Eugenin EA, Heary RF, Elkabes S (2019) Toll-like receptor 9 antagonism modulates astrocyte function and preserves proximal axons following spinal cord injury. Brain Behav Immun 80:328–343. https://doi.org/10.1016/j.bbi.2019.04.010

    Article  CAS  PubMed  Google Scholar 

  29. Lieder HR, Kleinbongard P, Skyschally A, Hagelschuer H, Chilian WM, Heusch G (2018) Vago-Splenic Axis in Signal Transduction of Remote Ischemic Preconditioning in Pigs and Rats. Circ Res 123:1152–1163. https://doi.org/10.1161/CIRCRESAHA.118.313859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu D, Zeng X, Li X, Mehta JL, Wang X (2018) Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res Cardiol 113:5. https://doi.org/10.1007/s00395-017-0663-9

    Article  CAS  PubMed  Google Scholar 

  31. Liu J, Cai X, Xie L, Tang Y, Cheng J, Wang J, Wang L, Gong J (2015) Circulating Cell Free Mitochondrial DNA is a Biomarker in the Development of Coronary Heart Disease in the Patients with Type 2 Diabetes. Clin Lab 61:661–667. https://doi.org/10.7754/clin.lab.2014.141132

    Article  CAS  PubMed  Google Scholar 

  32. Liu J, Jia Z, Gong W (2021) Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury. Front Immunol 12:680648. https://doi.org/10.3389/fimmu.2021.680648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426. https://doi.org/10.1016/s1097-2765(02)00599-3

    Article  CAS  PubMed  Google Scholar 

  34. Mastrocola R, Penna C, Tullio F, Femmino S, Nigro D, Chiazza F, Serpe L, Collotta D, Alloatti G, Cocco M, Bertinaria M, Pagliaro P, Aragno M, Collino M (2016) Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways. Oxid Med Cell Longev 2016:5271251. https://doi.org/10.1155/2016/5271251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mauler M, Herr N, Schoenichen C, Witsch T, Marchini T, Hardtner C, Koentges C, Kienle K, Ollivier V, Schell M, Dorner L, Wippel C, Stallmann D, Normann C, Bugger H, Walther P, Wolf D, Ahrens I, Lammermann T, Ho-Tin-Noe B, Ley K, Bode C, Hilgendorf I, Duerschmied D (2019) Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation. Circulation 139:918–931. https://doi.org/10.1161/CIRCULATIONAHA.118.033942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Menu P, Vince JE (2011) The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol 166:1–15. https://doi.org/10.1111/j.1365-2249.2011.04440.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan HR, Menna AC, Voelkel NF, Abbate A (2011) The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA 108:19725–19730. https://doi.org/10.1073/pnas.1108586108

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mildner CS, Copic D, Zimmermann M, Lichtenauer M, Direder M, Klas K, Bormann D, Gugerell A, Moser B, Hoetzenecker K, Beer L, Gyongyosi M, Ankersmit HJ, Laggner M (2022) Secretome of Stressed Peripheral Blood Mononuclear Cells Alters Transcriptome Signature in Heart, Liver, and Spleen after an Experimental Acute Myocardial Infarction: An In Silico Analysis. Biology (Basel). https://doi.org/10.3390/biology11010116

    Article  PubMed  Google Scholar 

  39. Peet C, Ivetic A, Bromage DI, Shah AM (2020) Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res 116:1101–1112. https://doi.org/10.1093/cvr/cvz336

    Article  CAS  PubMed  Google Scholar 

  40. Rein H (1949) Über ein Regulationssystem “Milz-Leber” für den oxydativen Stoffwechsel der Körpergewebe und besonders des Herzens. Naturwissenschaften 36:260–268. https://doi.org/10.1007/bf00584977

    Article  Google Scholar 

  41. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR (1983) Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67:1016–1023. https://doi.org/10.1161/01.cir.67.5.1016

    Article  CAS  PubMed  Google Scholar 

  42. Rusinkevich V, Huang Y, Chen ZY, Qiang W, Wang YG, Shi YF, Yang HT (2019) Temporal dynamics of immune response following prolonged myocardial ischemia/reperfusion with and without cyclosporine A. Acta Pharmacol Sin 40:1168–1183. https://doi.org/10.1038/s41401-018-0197-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saito Y, Hikita H, Nozaki Y, Kai Y, Makino Y, Nakabori T, Tanaka S, Yamada R, Shigekawa M, Kodama T, Sakamori R, Tatsumi T, Takehara T (2019) DNase II activated by the mitochondrial apoptotic pathway regulates RIP1-dependent non-apoptotic hepatocyte death via the TLR9/IFN-beta signaling pathway. Cell Death Differ 26:470–486. https://doi.org/10.1038/s41418-018-0131-6

    Article  CAS  PubMed  Google Scholar 

  44. Sandanger O, Gao E, Ranheim T, Bliksoen M, Kaasboll OJ, Alfsnes K, Nymo SH, Rashidi A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A (2016) NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun 469:1012–1020. https://doi.org/10.1016/j.bbrc.2015.12.051

    Article  CAS  PubMed  Google Scholar 

  45. Sandanger O, Ranheim T, Vinge LE, Bliksoen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A (2013) The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res 99:164–174. https://doi.org/10.1093/cvr/cvt091

    Article  CAS  PubMed  Google Scholar 

  46. Saxena A, Russo I, Frangogiannis NG (2016) Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res 167:152–166. https://doi.org/10.1016/j.trsl.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  47. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–414. https://doi.org/10.1016/j.immuni.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616. https://doi.org/10.1126/science.1175202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takahashi M (2019) Cell-Specific Roles of NLRP3 Inflammasome in Myocardial Infarction. J Cardiovasc Pharmacol 74:188–193. https://doi.org/10.1097/FJC.0000000000000709

    Article  CAS  PubMed  Google Scholar 

  50. Tian Y, Charles EJ, Yan Z, Wu D, French BA, Kron IL, Yang Z (2019) The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1-receptor for advanced glycation end products-Toll-like receptor 9 pathway. J Thorac Cardiovasc Surg 157:e2253. https://doi.org/10.1016/j.jtcvs.2018.09.043

    Article  CAS  Google Scholar 

  51. Tian Y, French BA, Kron IL, Yang Z (2015) Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice. Basic Res Cardiol 110:39. https://doi.org/10.1007/s00395-015-0496-3

    Article  CAS  PubMed  Google Scholar 

  52. Tian Y, Miao B, Charles EJ, Wu D, Kron IL, French BA, Yang Z (2018) Stimulation of the Beta2 Adrenergic Receptor at Reperfusion Limits Myocardial Reperfusion Injury via an Interleukin-10-Dependent Anti-Inflammatory Pathway in the Spleen. Circ J 82:2829–2836. https://doi.org/10.1253/circj.CJ-18-0061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tian Y, Pan D, Chordia MD, French BA, Kron IL, Yang Z (2016) The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE. Basic Res Cardiol 111:62. https://doi.org/10.1007/s00395-016-0583-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Toldo S, Mauro AG, Cutter Z, Van Tassell BW, Mezzaroma E, Del Buono MG, Prestamburgo A, Potere N, Abbate A (2019) The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse. J Cardiovasc Pharmacol 73:215–222. https://doi.org/10.1097/FJC.0000000000000658

    Article  CAS  PubMed  Google Scholar 

  55. Vakrakou AG, Boiu S, Ziakas PD, Xingi E, Boleti H, Manoussakis MN (2018) Systemic activation of NLRP3 inflammasome in patients with severe primary Sjogren’s syndrome fueled by inflammagenic DNA accumulations. J Autoimmun 91:23–33. https://doi.org/10.1016/j.jaut.2018.02.010

    Article  CAS  PubMed  Google Scholar 

  56. van der Laan AM, Ter Horst EN, Delewi R, Begieneman MP, Krijnen PA, Hirsch A, Lavaei M, Nahrendorf M, Horrevoets AJ, Niessen HW, Piek JJ (2014) 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. https://doi.org/10.1093/eurheartj/eht331

    Article  CAS  PubMed  Google Scholar 

  57. Vander Heide RS, Steenbergen C (2013) Cardioprotection and myocardial reperfusion: pitfalls to clinical application. Circ Res 113:464–477. https://doi.org/10.1161/CIRCRESAHA.113.300765

    Article  CAS  PubMed  Google Scholar 

  58. Wynn TA, Vannella KM (2016) Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity 44:450–462. https://doi.org/10.1016/j.immuni.2016.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, Endo J, Yamamoto T, Takeshima A, Shinmura K, Shen W, Fukuda K, Sano M (2013) Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J Mol Cell Cardiol 62:24–35. https://doi.org/10.1016/j.yjmcc.2013.04.023

    Article  CAS  PubMed  Google Scholar 

  60. Yang Z, Day Y-J, Toufektsian M-C, Ramos SI, Marshall M, Wang X-Q, French BA, Linden J (2005) Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes. Circulation 111:2190–2197

    Article  CAS  PubMed  Google Scholar 

  61. Yang Z, Day Y-J, Toufektsian M-C, Xu Y, Ramos SI, Marshall MA, French BA, Linden J (2006) Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114:2056–2064

    Article  CAS  PubMed  Google Scholar 

  62. Yang Z, Laubach VE, French BA, Kron IL (2009) Acute hyperglycemia enhances oxidative stress and exacerbates myocardial infarction by activating nicotinamide adenine dinucleotide phosphate oxidase during reperfusion. J Thorac Cardiovasc Surg 137:723–729. https://doi.org/10.1016/j.jtcvs.2008.08.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang Z, Linden J, Berr SS, Kron IL, Beller GA, French BA (2008) Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI. Am J Physiol Heart Circ Physiol 295:H2328-2335. https://doi.org/10.1152/ajpheart.00091.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. https://doi.org/10.1056/NEJMra071667

    Article  CAS  PubMed  Google Scholar 

  65. Zhang X, Qu H, Yang T, Kong X, Zhou H (2021) Regulation and functions of NLRP3 inflammasome in cardiac fibrosis: Current knowledge and clinical significance. Biomed Pharmacother 143:112219. https://doi.org/10.1016/j.biopha.2021.112219

    Article  CAS  PubMed  Google Scholar 

  66. Zindel J, Kubes P (2020) DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation. Annu Rev Pathol 15:493–518. https://doi.org/10.1146/annurev-pathmechdis-012419-032847

    Article  CAS  PubMed  Google Scholar 

  67. Zuurbier CJ (2019) NLRP3 Inflammasome in Cardioprotective Signaling. J Cardiovasc Pharmacol 74:271–275. https://doi.org/10.1097/FJC.0000000000000696

    Article  CAS  PubMed  Google Scholar 

  68. Zuurbier CJ, Jong WM, Eerbeek O, Koeman A, Pulskens WP, Butter LM, Leemans JC, Hollmann MW (2012) Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling. PLoS ONE 7:e40643. https://doi.org/10.1371/journal.pone.0040643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by awards from the National Natural Science Foundation of China (81870207 to YT, 82270470 to DL).

Author information

Author notes

  1. Dina Xie, Hanliang Guo, and Mingbiao Li contributed equally to this research.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Dina Xie, Hanliang Guo, Mingbiao Li, Liqun Jia, Hao Zhang, Degang Liang, Naishi Wu & Yikui Tian

  2. Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Yikui Tian

  3. Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Zequan Yang

Authors
  1. Dina Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanliang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingbiao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liqun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Degang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naishi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zequan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yikui Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yikui Tian.

Ethics declarations

Conflict of interest

None.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19893 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, D., Guo, H., Li, M. et al. Splenic monocytes mediate inflammatory response and exacerbate myocardial ischemia/reperfusion injury in a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion. Basic Res Cardiol 118, 44 (2023). https://doi.org/10.1007/s00395-023-01014-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-023-01014-0

Keywords

Search

Navigation