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Mono-macrophage-Derived MANF Alleviates Bacterial Myocarditis by Inhibiting NF-kappaB Activation and Myocardial Inflammation

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Abstract

Bacterial myocarditis is a key cause leading to myocardial damage and cardiac dysfunction. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been found to be an anti-inflammatory factor. This study is to explore the effect of MANF on LPS-induced myocardial inflammation and macrophage differentiation. The myocarditis mouse model was constructed by LPS treatment. Myocardial damage and serum inflammatory factors were evaluated by ELISA. RT-qPCR was used to detect mRNA of M1/M2 macrophage markers. Western blot, immunohistochemical, and immunofluorescent staining were used to examine myocardial M1/M2 macrophages and NF-κB activation. Mono-macrophage-derived MANF deficiency enhanced LPS-induced inflammatory response and increased M1 macrophages in myocardium tissues, further causing more severe myocardial injury and lower survival rate of mice. Also, LPS-induced myocardial NF-κB activation was strengthened after mono-macrophage-derived MANF knockout. Mono-macrophage-derived MANF inhibits bacterial myocarditis and myocardial M1 macrophage differentiation, which is potential to be used for bacterial myocarditis treatment clinically.

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Data Availability

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Abbreviations

MANF:

Mesencephalic astrocyte-derived neurotrophic factor

Mø:

Macrophage

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

iNOS :

Inducible nitric oxide synthase

ER:

Endoplasmic reticulum

References

  1. Alam, S., Q. Liu, S. Liu, Y.N. Liu, Y.L. Zhang, X.H. Yang, G. Liu, K. Fan, and J.M. Ma. 2019. Up-regulated cathepsin C induces macrophage M1 polarization through FAK-triggered p38 MAPK/NF-kappa B pathway. Experimental Cell Research 382 (2-3): 9. https://doi.org/10.1016/j.yexcr.2019.06.017.

    Article  CAS  Google Scholar 

  2. Apostolou, Andria, Yuxian Shen, Yan Liang, Jun Luo, and Shengyun Fang. 2008. Armet, a UPR-upregulated protelin, inhibits cell proliferation and ER stress-induced cell death. Experimental Cell Research 314 (13): 2454–2467. https://doi.org/10.1016/j.yexcr.2008.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arrieta, A., W.T. Stauffer, A.N. Pentoney, E.A. Blackwood, S. Doroudgar, and C.C. Glembotski. 2016. MANF, a Structurally Unique ER Stress-inducible Protein, Restores ER-protein Folding in ER Stressed Cardiac Myocytes and in the Ischemic Heart. Circulation Research 119: 2.

    Article  Google Scholar 

  4. Chen, Lijian, Lijie Feng, Xia Wang, Du Jian, Ying Chen, Wen Yang, Chengyue Zhou, et al. 2015. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Involved in Inflammation by Negatively Regulating the NF-kappa B Pathway. Scientific Reports 5. https://doi.org/10.1038/srep08133.

  5. Chen, Y.N., M.R. Hu, L. Wang, and W.D. Chen. 2020. Macrophage M1/M2 polarization. European Journal of Pharmacology 877: 9. https://doi.org/10.1016/j.ejphar.2020.173090.

    Article  CAS  Google Scholar 

  6. Epelman, Slava, Kory J. Lavine, and Gwendalyn J. Randolph. 2014. Origin and Functions of Tissue Macrophages. Immunity 41 (1): 21–35. https://doi.org/10.1016/j.immuni.2014.06.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hakonen, E., V. Chandra, C.L. Fogarty, N.Y.L. Yu, J. Ustinov, S. Katayama, E. Galli, T. Danilova, P. Lindholm, A. Vartiainen, E. Einarsdottir, K. Krjutškov, J. Kere, M. Saarma, M. Lindahl, and T. Otonkoski. 2018. MANF protects human pancreatic beta cells against stress-induced cell death. Diabetologia 61 (10): 2202–2214. https://doi.org/10.1007/s00125-018-4687-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hanna, Anis, and Nikolaos G. Frangogiannis. 2020. Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure. Cardiovascular Drugs and Therapy 34: 849–863. https://doi.org/10.1007/s10557-020-07071-0.

    Article  CAS  PubMed  Google Scholar 

  9. Hou, Chao, Wang Dong, Xiang Li, Yufeng He, Chuansheng Wei, Rong Jiang, Jun Liu, Lijie Feng, and Yuxian Shen. 2019. MANF regulates splenic macrophage differentiation in mice. Immunology Letters 212: 37–45. https://doi.org/10.1016/j.imlet.2019.06.007.

    Article  CAS  PubMed  Google Scholar 

  10. Italiani, P., and D. Boraschi. 2014. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Frontiers in Immunology 5: 22. https://doi.org/10.3389/fimmu.2014.00514.

    Article  CAS  Google Scholar 

  11. Kim, Y., S.J. Park, and Y.M. Chen. 2017. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles. Translational Research 188: 1–9. https://doi.org/10.1016/j.trsl.2017.06.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Komuro, J., K. Ueda, M. Kaneko, S. Nitta, M. Kasao, and M. Yokoyama. 2018. Various Cardiac Abnormalities Caused by Bacterial Myocarditis. International Heart Journal 59 (1): 229–232. https://doi.org/10.1536/ihj.16-651.

    Article  PubMed  Google Scholar 

  13. Li, M.H., Y.W. Gou, H.M. Yu, T.F. Ji, Y. Li, L. Qin, and W. Sun. 2019. Mechanism of Metformin on LPS-Induced Bacterial Myocarditis. Dose-Response 17 (2): 9. https://doi.org/10.1177/1559325819847409.

    Article  CAS  Google Scholar 

  14. Li, Q., Z.G. Dai, Y.Z. Cao, and L.H. Wang. 2019. Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-kappa B activation. Biochemical and Biophysical Research Communications 513 (2): 479–485. https://doi.org/10.1016/j.bbrc.2019.03.202.

    Article  CAS  PubMed  Google Scholar 

  15. Liu, C.P., X. Zhang, Q.L. Tan, W.X. Xu, C.Y. Zhou, M. Luo, X. Li, R.Y. Huang, and X. Zeng. 2017. NF-kappa B pathways are involved in M1 polarization of RAW 264.7 macrophage by polyporus polysaccharide in the tumor microenvironment. PLoS One 12 (11): 16. https://doi.org/10.1371/journal.pone.0188317.

    Article  CAS  Google Scholar 

  16. Liu, J., X.F. Tao, J. Zhang, P. Wang, M.Q. Sha, Y. Ma, X.P. Geng, et al. 2016. Small ubiquitin-related modifier 1 is involved in hepatocellular carcinoma progression via mediating p65 nuclear translocation. Oncotarget 7 (16): 22206–22218. https://doi.org/10.18632/oncotarget.8066.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liu, J., C.Y. Zhou, X.F. Tao, L.J. Feng, X. Wang, L.J. Chen, C.J. Li, D.K. Huang, S.Y. Fang, and Y.X. Shen. 2015. ER stress-inducible protein MANF selectively expresses in human spleen. Human Immunology 76 (11): 823–830. https://doi.org/10.1016/j.humimm.2015.09.043.

    Article  CAS  PubMed  Google Scholar 

  18. Liu, L.L., H.M. Guo, A.M. Song, J.H. Huang, Y. Zhang, S.S. Jin, S.T. Li, L.G. Zhang, C.Z. Yang, and P.S. Yang. 2020. Progranulin inhibits LPS-induced macrophage M1 polarization via NF-kB and MAPK pathways. BMC Immunology 21 (1): 12. https://doi.org/10.1186/s12865-020-00355-y.

    Article  CAS  Google Scholar 

  19. Liu, S.F., and A.B. Malik. 2006. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. American Journal of Physiology. Lung Cellular and Molecular Physiology 290 (4): L622–L645. https://doi.org/10.1152/ajplung.00477.2005.

    Article  CAS  PubMed  Google Scholar 

  20. Matlik, K., J.E. Anttila, T. Kuan-Yin, O.P. Smolander, E. Pakarinen, L. Lehtonen, U. Abo-Ramadan, et al. 2018. Poststroke delivery of MANF promotes functional recovery in rats. Science Advances 4 (5): 8. https://doi.org/10.1126/sciadv.aap8957.

    Article  CAS  Google Scholar 

  21. Neves, J., K.R. Chirco, W. Cedron-Craft, S. Chew, J. Zhu, H. Jasper, and D.A. Lamba. 2020. MANF delivery improves retinal homeostasis and cell replacement therapies in ageing mice. Experimental Gerontology 134: 10. https://doi.org/10.1016/j.exger.2020.110893.

    Article  CAS  Google Scholar 

  22. Neves, Joana, Jie Zhu, Pedro Sousa-Victor, Mia Konjikusic, Rebeccah Riley, Shereen Chew, Yanyan Qi, Heinrich Jasper, and Deepak A. Lamba. 2016. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science 353 (6294): 43-+. https://doi.org/10.1126/science.aaf3646.

    Article  CAS  Google Scholar 

  23. Pan, Deng, Jesus A. Acevedo-Cintron, Junichi Sayanagi, Alison K. Snyder-Warwick, Susan E. Mackinnon, and Matthew D. Wood. 2020. The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration. Experimental Neurology 331: 113363. https://doi.org/10.1016/j.expneurol.2020.113363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shen, Yujun, Aimin Sun, Yunhong Wang, Daqin Cha, Haiping Wang, Facai Wang, Lijie Feng, Shengyun Fang, and Yuxian Shen. 2012. Upregulation of mesencephalic astrocyte-derived neurotrophic factor in glial cells is associated with ischemia-induced glial activation. Journal of Neuroinflammation 9. https://doi.org/10.1186/1742-2094-9-254.

  25. Smith, S.C., J.H. Ladenson, J.W. Mason, and A.S. Jaffe. 1997. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates. Circulation 95 (1): 163–168. https://doi.org/10.1161/01.cir.95.1.163.

    Article  CAS  PubMed  Google Scholar 

  26. Strassheim, D., E.C. Dempsey, E. Gerasimovskaya, K. Stenmark, and V. Karoor. 2019. Role of Inflammatory Cell Subtypes in Heart Failure. Journal of Immunology Research 2019: 9. https://doi.org/10.1155/2019/2164017.

    Article  CAS  Google Scholar 

  27. Stratoulias, V., and T.I. Heino. 2015. MANF silencing, immunity induction or autophagy trigger an unusual cell type in metamorphosing Drosophila brain. Cellular and Molecular Life Sciences 72 (10): 1989–2004. https://doi.org/10.1007/s00018-014-1789-7.

    Article  CAS  PubMed  Google Scholar 

  28. Tadimalla, A., P.J. Belmont, D.J. Thuerauf, M.S. Glassy, J.J. Martindale, N. Gude, M.A. Sussman, and C.C. Glembotski. 2008. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is an Ischemia-Inducible Secreted Endoplasmic Reticulum Stress Response Protein in the Heart. Circulation Research 103 (11): 1249–1258. https://doi.org/10.1161/circresaha.108.180679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tseng, K.Y., J.E. Anttila, K. Khodosevich, R.K. Tuominen, M. Lindahl, A. Domanskyi, and M. Airavaara. 2018. MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke. Molecular Therapy 26 (1): 238–255. https://doi.org/10.1016/j.ymthe.2017.09.019.

    Article  CAS  PubMed  Google Scholar 

  30. Vadivel, S., P. Vincent, S. Sekaran, S.V. Ambi, S. Muralidar, V. Selvaraj, B. Palaniappan, and D. Thirumalai. 2020. Inflammation in myocardial injury- Stem cells as potential immunomodulators for myocardial regeneration and restoration. Life Sciences 250: 15. https://doi.org/10.1016/j.lfs.2020.117582.

    Article  CAS  Google Scholar 

  31. Wang, C.H., S.J. Yu, Q. Bao, W.M. Qiang, C.R. Wu, C.X. Zhang, Y. Jiang, et al. 2020. Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Negatively Correlates With Atrial Apoptosis in Human Chronic Atrial Fibrillation. Journal of Cardiovascular Pharmacology 75 (2): 141–147. https://doi.org/10.1097/fjc.0000000000000781.

    Article  CAS  PubMed  Google Scholar 

  32. Wang, J., Q.Y. Cheng, and X. Wang. 2015. Deficiency of IRE1 and PERK Signal Pathways in Systemic Lupus Erythematosus (vol 348, pg 465, 2014). American Journal of the Medical Sciences 349 (3): 285–285.

    Article  Google Scholar 

  33. Wang, X.C., W.N. Li, Q.J. Zhou, J. Li, X.L. Wang, J. Zhang, D.W. Li, et al. 2020. MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress. Diabetes 69 (6): 1264–1278. https://doi.org/10.2337/db19-0835.

    Article  CAS  PubMed  Google Scholar 

  34. Wang, Y., S.X. Zhao, Y. Chen, Y. Wang, T.Y. Wang, X.M. Wo, Y.Y. Dong, et al. 2020. N-Acetyl cysteine effectively alleviates Coxsackievirus B-Induced myocarditis through suppressing viral replication and inflammatory response. Antiviral Research 179: 13. https://doi.org/10.1016/j.antiviral.2019.104699.

    Article  CAS  Google Scholar 

  35. Yang, H., Q.N. Zhang, M. Xu, L. Wang, X.W. Chen, Y.Q. Feng, Y.N. Li, X. Zhang, W.M. Cui, and X.D. Jia. 2020. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Molecular Cancer 19 (1): 14. https://doi.org/10.1186/s12943-020-01165-x.

    Article  CAS  Google Scholar 

  36. Yang, Wen, Yujun Shen, Ying Chen, Chen Lu, Le Wang, Haiping Wang, Shengchun Xu, et al. 2014. Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis. Journal of the Neurological Sciences 344 (1-2): 129–138. https://doi.org/10.1016/j.jns.2014.06.042.

    Article  CAS  PubMed  Google Scholar 

  37. Yu, Yong-Qiang, Lian-Cheng Liu, Fa-Cai Wang, Yan Liang, Da-Qin Cha, Jing-Jing Zhang, Yu-Jun Shen, Hai-Ping Wang, Shengyun Fang, and Yu-Xian Shen. 2010. Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. Journal of Cerebral Blood Flow and Metabolism 30 (1): 79–91. https://doi.org/10.1038/jcbfm.2009.181.

    Article  CAS  PubMed  Google Scholar 

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Funding

Thestudy was financially supported by the fund from National Natural ScienceFoundation of China to Dong Wang [Grant Number: 31800702],Qiying Shen [Grant Number: 81902003] and Ye Zhao [Grant Number: 31600680,81673099], and the fund from the Natural Science Foundation of University ofAnhui Province to Changhui Wang [Grant Number: KJ2019A0265], theGrant for Scientifific Research of BSKY from the First Affiliated Hospital ofAnhui Medical University to Changhui Wang [Grant Number: BSKY2019003] and the Grantfrom Anhui Medical University to Changhui Wang [Grant Number: 2020xkj158].

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Author notes

  1. Changhui Wang and Qin Bao contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China

    Changhui Wang, Shiyu Cao & Xinyu Wang

  2. School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China

    Qin Bao, Chao Hou, Minqiong Sun, Xuegang Song, Ye Zhao & Dong Wang

  3. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China

    Qiying Shen

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  1. Changhui Wang
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Contributions

D.W. and Y. Z. designed the research and wrote the manuscript; C. H. W., Q. B., C. H., M. Q. S., X. G. S., S. Y. C., and X. Y. W. performed the experiments; Q. Y. S. collected and analyzed the data.

Corresponding authors

Correspondence to Qiying Shen, Ye Zhao or Dong Wang.

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All mice studies were conducted according to protocols approved by the Animal Ethics Committee of Anhui Medical University with the approval number: LLSC20200022.

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Wang, C., Bao, Q., Hou, C. et al. Mono-macrophage-Derived MANF Alleviates Bacterial Myocarditis by Inhibiting NF-kappaB Activation and Myocardial Inflammation. Inflammation 44, 1916–1926 (2021). https://doi.org/10.1007/s10753-021-01469-0

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