Skip to main content

Advertisement

Log in

Focus on the Multimodal Role of Autophagy in Rheumatoid Arthritis

  • Review
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Autophagy exerts its dual role in eukaryotic cells and exerts its cytoprotective action through degradation mechanism and by regulating catabolic processes which results in elimination of pathogens. Under suitable conditions, autophagy is associated with recycling of cytoplasmic components which causes regeneration of energy whereas deregulated autophagy exerts its implicated role in development and pathogenesis of auto-immune diseases such as rheumatoid arthritis. The immune, innate, and adaptive responses are regulated through the development, proliferation, and growth of lymphocytes. Such innate and adaptive responses can act as mediator of arthritis; along with this, stimulation of osteoclast-mediated bone resorption takes place via transferring citrullinated peptides towards MHC (major histocompatibility complex) compartments, thereby resulting in degradation of bone. Processes such as apoptosis resistance are also regulated through autophagy. In this review, the current knowledge based on role of autophagy in pathogenesis of rheumatoid arthritis is summarized along with proteins associated.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Dikic, Ivan. 2017. Proteasomal and autophagic degradation systems. Annual Review of Biochemistry 86: 193–224. https://doi.org/10.1146/annurev-biochem-061516-044908.

    Article  CAS  PubMed  Google Scholar 

  2. Zappavigna, S., A. Luce, G. Vitale, N. Merola, S. Facchini, and M. Caraglia. 2013. Autophagic cell death: a new frontier in cancer research. Advances in Bioscience and Biotechnology 4 (2): 250–262. https://doi.org/10.4236/abb.2013.42034.

    Article  CAS  Google Scholar 

  3. Yin, Zhangyuan, Clarence Pascual, and Daniel J. Klionsky. 2016. Autophagy: machinery and regulation. Microbial cell 3 (12): 588. https://doi.org/10.15698/mic2016.12.546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ventruti, Annamaria, and Ana Maria Cuervo. 2007. Autophagy and neurodegeneration. Current Neurology and Neuroscience Reports 7 (5): 443–451. https://doi.org/10.1080/15548627.2020.1725377.

    Article  CAS  PubMed  Google Scholar 

  5. Yao, Ren-Qi, Chao Ren, Zhao-Fan Xia, and Yong-Ming Yao. 2020. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 1-17: 1–17. https://doi.org/10.1080/15548627.2020.1725377.

    Article  CAS  Google Scholar 

  6. Mizushima, Noboru, and Masaaki Komatsu. 2011. Autophagy: renovation of cells and tissues. Cell. 147 (4): 728–741. https://doi.org/10.1016/j.cell.2011.10.026.

    Article  CAS  PubMed  Google Scholar 

  7. Kaushik, Susmita, and Ana Maria Cuervo. 2020. Protein degradation and the lysosomal system. In The Liver: Biology and Pathobiology, 122–136. https://doi.org/10.1002/9781119436812.ch11.

    Chapter  Google Scholar 

  8. Rubinsztein, David C., Guillermo Mariño, and Guido Kroemer. 2011. Autophagy and aging. Cell. 146 (5): 682–695. https://doi.org/10.1016/j.cell.2011.07.030.

    Article  CAS  PubMed  Google Scholar 

  9. Gerónimo-Olvera, Cristian, and Lourdes Massieu. 2019. Autophagy as a homeostatic mechanism in response to stress conditions in the central nervous system. Molecular Neurobiology 56 (9): 6594–6608.

    Article  PubMed  CAS  Google Scholar 

  10. Galluzzi, Lorenzo, José Manuel Bravo-San Pedro, Beth Levine, Douglas R. Green, and Guido Kroemer. 2017. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nature Reviews. Drug Discovery 16 (7): 487–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guo, Qiang, Yuxiang Wang, Dan Xu, Johannes Nossent, Nathan J. Pavlos, and Xu. Jiake. 2018. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Research. 6 (1): 1–14.

    Article  CAS  Google Scholar 

  12. Meijer, Alfred J., and Patrice Codogno. 2009. Autophagy: regulation and role in disease. Critical Reviews in Clinical Laboratory Sciences 46 (4): 210–240. https://doi.org/10.1080/10408360903044068.

    Article  CAS  PubMed  Google Scholar 

  13. Mijaljica, Prescott M., and R. Devenish. 2010. Autophagy in disease. In Protein Mis-folding and Cell Stress Dis and Aging, 79–92.

    Google Scholar 

  14. Wesselborg, Sebastian, and Björn Stork. 2015. Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cellular and Molecular Life Sciences 72 (24): 4721–4757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim, Sang Gyun, Gwen R. Buel, and John Blenis. 2013. Nutrient regulation of the mTOR complex 1 signaling pathway. Molecules and Cells 35 (6): 463–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Meijer, Alfred J., Séverine Lorin, Edward F. Blommaart, and Patrice Codogno. 2015. Regulation of autophagy by amino acids and mTOR-dependent signal transduction. Amino Acids 47 (10): 2037–2063.

    Article  CAS  PubMed  Google Scholar 

  17. Kim, Joungmok, and Kun-Liang Guan. 2011. Amino acid signaling in TOR activation. Annual Review of Biochemistry 80: 1001–1032. https://doi.org/10.1146/annurev-biochem-062209-094414.

    Article  CAS  PubMed  Google Scholar 

  18. Hale, Amber N., Dan J. Ledbetter, Thomas R. Gawriluk, and Edmund B. Rucker III. 2013. Autophagy: regulation and role in development. Autophagy. 9 (7): 951–972. https://doi.org/10.4161/auto.24273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noda, Takeshi, Kohichi Matsunaga, Naoko Taguchi-Atarashi, and Tamotsu Yoshimori. 2010. Regulation of membrane biogenesis in autophagy via PI3P dynamics. Seminars in Cell & Developmental Biology 21 (70): 671–676. https://doi.org/10.1016/j.semcdb.2010.04.002.

    Article  CAS  Google Scholar 

  20. Tooze, Sharon A., and Tamotsu Yoshimori. 2010. The origin of the autophagosomal membrane. Nature Cell Biology 12 (9): 831–835.

    Article  CAS  PubMed  Google Scholar 

  21. Abounit, Kadija, Tiziano M. Scarabelli, and Roy B. McCauley. 2012. Autophagy in mammalian cells. World Journal of Biological Chemistry 3 (1): 1–6. https://doi.org/10.4331/wjbc.v3.i1.1.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kang, R., H.J. Zeh, M.T. Lotze, and D. Tang. 2011. The Beclin 1 network regulates autophagy and apoptosis. Cell Death and Differentiation 18 (4): 571–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mukhopadhyay, Subhadip, Prashanta Kumar Panda, Niharika Sinha, Durgesh Nandini Das, and Sujit Kumar Bhutia. 2014. Autophagy and apoptosis: where do they meet? Apoptosis. 19 (4): 555–566.

    Article  CAS  PubMed  Google Scholar 

  24. Peng, Hong, Jiao Yang, Guangyi Li, Qing You, Wen Han, Tianrang Li, Daming Gao, Xiaoduo Xie, Byung-Hoon Lee, Juan du, Jian Hou, Tao Zhang, Hai Rao, Ying Huang, Qinrun Li, Rong Zeng, Lijian Hui, Hongyan Wang, Qin Xia, Xuemin Zhang, Yongning He, Masaaki Komatsu, Ivan Dikic, Daniel Finley, and Ronggui Hu. 2017. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Research 27 (5): 657–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanida, Isei, and Satoshi Waguri. 2010. Measurement of autophagy in cells and tissues. In Protein Misfolding and Cellular Stress in Disease and Aging, 193–214.

    Chapter  Google Scholar 

  26. Menzies, Fiona, Angeleen Fleming, Andrea Caricasole, Carla F. Bento, Stephen P. Andrews, Avraham Ashkenazi, Jens Füllgrabe, et al. 2017. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 93 (5): 1015–1034. https://doi.org/10.1016/j.neuron.2017.01.022.

    Article  CAS  PubMed  Google Scholar 

  27. Levine, Beth, and Guido Kroemer. 2019. Biological functions of autophagy genes: a disease perspective. Cell. 176 (1–2): 11–42. https://doi.org/10.1016/j.cell.2018.09.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Batlevi, Yakup, and Albert R. La Spada. 2011. Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiology of Disease 43 (1): 46–51. https://doi.org/10.1016/j.nbd.2010.09.009.

    Article  CAS  PubMed  Google Scholar 

  29. Nixon, Ralph A. 2013. The role of autophagy in neurodegenerative disease. Nature Medicine 19 (8): 983–997.

    Article  CAS  PubMed  Google Scholar 

  30. Wen, Xin, Jinming Wu, Fengtian Wang, Bo Liu, Canhua Huang, and Yuquan Wei. 2013. Deconvoluting the role of reactive oxygen species and autophagy in human diseases. Free Radical Biology & Medicine 65: 402–410. https://doi.org/10.1016/j.freeradbiomed.2013.07.013.

    Article  CAS  Google Scholar 

  31. Dewaele, Michael, Hannelore Maes, and Patrizia Agostinis. 2010. ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy. 6 (7): 838–854. https://doi.org/10.4161/auto.6.7.12113.

    Article  CAS  PubMed  Google Scholar 

  32. Toton, E., N. Lisiak, P. Sawicka, and M. Rybczynska. 2014. Beclin-1 and its role as a target for anticancer therapy. Journal of Physiology and Pharmacology 65 (4): 459–467.

    CAS  PubMed  Google Scholar 

  33. Daskalaki, Ioanna, Ilias Gkikas, and Nektarios Tavernarakis. 2018. Hypoxia and selective autophagy in cancer development and therapy. Frontiers in Cell and Development Biology 6: 104.

    Article  Google Scholar 

  34. Petibone, Dayton M., Waqar Majeed, and Daniel A. Casciano. 2017. Autophagy function and its relationship to pathology, clinical applications, drug metabolism and toxicity. Journal of Applied Toxicology 37 (1): 23–37. https://doi.org/10.1002/jat.3393.

    Article  CAS  PubMed  Google Scholar 

  35. Kuballa, Petric, Whitney M. Nolte, Adam B. Castoreno, and Ramnik J. Xavier. 2012. Autophagy and the immune system. Annual Review of Immunology 30: 611–646.

    Article  CAS  PubMed  Google Scholar 

  36. Takahama, Michihiro, Shizuo Akira, and Tatsuya Saitoh. 2018. Autophagy limits activation of the inflammasomes. Immunological Reviews 281 (1): 62–73. https://doi.org/10.1111/imr.12613.

    Article  CAS  PubMed  Google Scholar 

  37. Yu, Xiaowen, Chunmei Li, Weiling Hong, Weihua Pan, and Jianping Xie. 2013. Autophagy during mycobacterium tuberculosis infection and implications for future tuberculosis medications. Cellular signaling. 25 (5): 1272–1278. https://doi.org/10.1016/j.cellsig.2013.02.011.

    Article  CAS  Google Scholar 

  38. Meyer, De, Wim Martinet Inge, Dorien M. Schrijvers, Jean-Pierre Timmermans, Hidde Bult, and Guido R.Y. De Meyer. 2012. Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques. Basic Research in Cardiology 107 (3): 269.

    Article  PubMed  CAS  Google Scholar 

  39. Andrade, Rosa M., Matthew Wessendarp, Marc-Jan Gubbels, Boris Striepen, and Carlos S. Subauste. 2006. CD40 induces macrophage anti–Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. The Journal of clinical investigation. 116 (9): 2366–2377. https://doi.org/10.1172/JCI28796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baregamian, Naira, Song Jun, C. Eric Bailey, Papaconstantinou John, B. Mark Evers, and Dai H. Chung. 2009. Tumor necrosis factor-α and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxidative Medicine and Cellular Longevity 2 (5): 297–306.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Harris, James, and Joseph Keane. 2010. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clinical and Experimental Immunology 161 (1): 1–9. https://doi.org/10.1111/j.1365-2249.2010.04146.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Keller, Christian W., Claudia Fokken, Stuart G. Turville, Anna Lünemann, Jens Schmidt, Christian Münz, and Jan D. Lünemann. 2011. TNF-α induces macroautophagy and regulates MHC class II expression in human skeletal muscle cells. The Journal of Biological Chemistry 286 (5): 3970–3980.

    Article  CAS  PubMed  Google Scholar 

  43. Ling, Yun M., Michael H. Shaw, Carol Ayala, Isabelle Coppens, Gregory A. Taylor, David J.P. Ferguson, and George S. Yap. 2006. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. The Journal of experimental medicine. 203 (9): 2063–2071. https://doi.org/10.1084/jem.20061318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hua, Fang, Ke Li, Shuang Shang, Feng Wang, and Hu. Zhuowei. 2019. Immune signaling and autophagy regulation. In Autophagy: Biology and Diseases, 551–593.

    Chapter  Google Scholar 

  45. Park, Hun-Jung, Suk Jun Lee, Sang-Hoon Kim, Jihye Han, Joonbeom Bae, Sang Joon Kim, Chung-Gyu Park, and Taehoon Chun. 2011. IL-10 inhibits the starvation induced autophagy in macrophages via class I phosphatidylinositol 3-kinase (PI3K) pathway. Molecular Immunology 48 (4): 720–727.

    Article  CAS  PubMed  Google Scholar 

  46. Grol, Van, Cecilia Subauste Jennifer, Rosa M. Andrade, Koh Fujinaga, Julie Nelson, and Carlos S. Subauste. 2010. HIV-1 inhibits autophagy in bystander macrophage/monocytic cells through Src-Akt and STAT3. Public Library of Science one. 5 (7): e11733. https://doi.org/10.1371/journal.pone.0011733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Petiot, Anne, Eric Ogier-Denis, Edward F.C. Blommaart, Alfred J. Meijer, and Patrice Codogno. 2000. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. The Journal of Biological Chemistry 275 (2): 992–998.

    Article  CAS  PubMed  Google Scholar 

  48. Ni Cheallaigh, C., Joseph Keane, Ed C. Lavelle, Jayne C. Hope, and James Harris. 2011. Autophagy in the immune response to tuberculosis: clinical perspectives. Clinical and Experimental Immunology 164 (3): 291–300. https://doi.org/10.1111/j.1365-2249.2011.04381.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Suzuki, Hiroshi I., Kunihiko Kiyono, and Kohei Miyazono. 2010. Regulation of autophagy by transforming growth factor-β (TGF-β) signaling. Autophagy. 6 (5): 645–647. https://doi.org/10.4161/auto.6.5.12046.

    Article  PubMed  Google Scholar 

  50. Roca, Hernan, Zachary S. Varsos, Sudha Sud, Matthew J. Craig, Chi Ying, and Kenneth J. Pienta. 2009. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. The Journal of Biological Chemistry 284 (49): 34342–34354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shi, Chong-Shan, and John H. Kehrl. 2008. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. The Journal of Biological Chemistry 283 (48): 33175–33182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bhatnagar, Shephali, Ashwani Mittal, Sanjay K. Gupta, and Ashok Kumar. 2012. TWEAK causes myotube atrophy through coordinated activation of ubiquitin-proteasome system, autophagy, and caspases. Journal of Cellular Physiology 227 (3): 1042–1051. https://doi.org/10.1002/jcp.22821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Crişan, Tania, Theo S. Plantinga, Frank L. van de Veerdonk, Marius F. Farcaş, Monique Stoffels, Bart-Jan Kullberg, Jos W.M. van der Meer, Leo A.B. Joosten, and Mihai G. Netea. 2011. Inflammasome-independent modulation of cytokine response by autophagy in human cells. Public Library of Science one 6 (4): e18666. https://doi.org/10.1371/journal.pone.0018666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. James, Harris, Michelle Hartman, Caitrionna Roche, Shijuan G. Zeng, Amy O'Shea, Fiona A. Sharp, and Eimear M. Lambe. 2011. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. Journal of Biological Chemistry 286 (11): 9587–9597.

    Article  CAS  Google Scholar 

  55. Tatsuya, Saitoh, Naonobu Fujita, Myoung Ho Jang, Satoshi Uematsu, Bo-Gie Yang, Takashi Satoh, and Hiroko Omori. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 456 (7219): 264–268.

    Article  CAS  Google Scholar 

  56. Rongbin, Zhou, Amir S. Yazdi, Philippe Menu, and Jürg Tschopp. 2011. A role for mitochondria in NLRP3 inflammasome activation. Nature. 469 (7329): 221–225.

    Article  CAS  Google Scholar 

  57. Schroder, Kate, and Jurg Tschopp. 2010. The inflammasomes. Cell 140 (6): 821–832. https://doi.org/10.1016/j.cell.2010.01.040.

    Article  CAS  PubMed  Google Scholar 

  58. Behl Tapan, and Priya Nijhawan. 2020. Role of Endostatin in Rheumatoid Arthritis. Current Rheumatology Reviews. 16(4):1–20. https://doi.org/10.2174/1573397115666191127141801.

  59. Karsten, Conrad, Dirk Roggenbuck, Dirk Reinhold, and Thomas Dörner. 2010. Profiling of rheumatoid arthritis associated autoantibodies. Autoimmunity Reviews 9 (6): 431–435. https://doi.org/10.1016/j.autrev.2009.11.017.

    Article  CAS  Google Scholar 

  60. McInnes Iain, B., and Georg Schett. 2011. The pathogenesis of rheumatoid arthritis. The New England Journal of Medicine 365 (23): 2205–2219. https://doi.org/10.1056/NEJMra1004965.

    Article  CAS  PubMed  Google Scholar 

  61. Guido, Valesini, Maria C. Gerardi, Cristina Iannuccelli, Viviana A. Pacucci, Monica Pendolino, and Yehuda Shoenfeld. 2015. Citrullination and autoimmunity. Autoimmunity Reviews 14 (6): 490–497. https://doi.org/10.1016/j.autrev.2015.01.013.

    Article  CAS  Google Scholar 

  62. Germic, Nina, Ziva Frangez, Shida Yousefi, and Hans-Uwe Simon. 2019. Regulation of the innate immune system by autophagy: monocytes, macrophages, dendritic cells and antigen presentation. Cell Death and Differentiation 26 (4): 715–727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, Z., and Weyand Goronzy. 2015. Autophagy in autoimmune disease. Journal of Molecular Medicine 93 (7): 707–717.

    Article  CAS  PubMed  Google Scholar 

  64. Zhu Li, Huaizhou Wang, Yu Wu, Zhengwen He, Yanghua Qin, and Qian Shen. 2017. The autophagy level is increased in the synovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators of inflammation. 2017: 1–9. https://doi.org/10.1155/2017/7623145.

  65. Caramés, Beatriz, Akihiko Hasegawa, Noboru Taniguchi, Shigeru Miyaki, Francisco J. Blanco, and Martin Lotz. 2012. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Annals of the Rheumatic Diseases 71 (4): 575–581.

    Article  PubMed  CAS  Google Scholar 

  66. DeSelm, Carl, Brian Miller, Wei Zou, Wandy L. Beatty, Eline van Meel, Yoshifumi Takahata, Judith Klumperman, Sharon A. Tooze, Steven L. Teitelbaum, and Herbert W. Virgin. 2011. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Developmental Cell 21 (5): 966–974. https://doi.org/10.1016/j.devcel.2011.08.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Marina, Pierdominici, Marta Vomero, Cristiana Barbati, Tania Colasanti, Angela Maselli, Davide Vacirca, Antonello Giovannetti, Walter Malorni, and Elena Ortona. 2012. Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. The Federation of American Societies for Experimental Biology Journal 26 (4): 1400–1412. https://doi.org/10.3389/fimmu.2018.01577.

    Article  CAS  Google Scholar 

  68. Maurer, Katie, Tamara Reyes-Robles, Joan Durbin Francis Alonzo III, Victor J. Torres, and Ken Cadwell. 2015. Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin. Cell Host & Microbe 17 (4): 429–440. https://doi.org/10.1016/j.chom.2015.03.001.

    Article  CAS  Google Scholar 

  69. Ludger, Klein, Christian Münz, and Jan D. Lünemann. 2010. Autophagy-mediated antigen processing in CD4+ T cell tolerance and immunity. Federation of European Biochemical Societies letters 584 (7): 1405–1410. https://doi.org/10.1016/j.febslet.2010.01.008.

    Article  CAS  Google Scholar 

  70. Manon, Wildenberg, Anne Christine Vos, Simone C.S. Wolfkamp, Marjolijn Duijvestein, Auke P. Verhaar, Anje A. Te Velde, Gijs R. van den Brink, and Daniel W. Hommes. 2012. Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse. Gastroenterology 142 (7): 1493–1503. https://doi.org/10.3390/jcm6070073.

    Article  CAS  Google Scholar 

  71. Motomu, Hashimoto. 2017. Th17 in animal models of rheumatoid arthritis. Journal of Clinical Medicine 6 (7): 73. https://doi.org/10.3390/jcm6070073.

    Article  CAS  Google Scholar 

  72. Azizi, Gholamreza, Mohsen Rastegar Pouyani, Shadi Sadat Navabi, Reza Yazdani, Fatemeh Kiaee, and Abbas Mirshafiey. 2015. The newly identified T helper 22 cells lodge in leukemia. International journal of hematology-oncology and stem cell research 9 (3): 143.

    PubMed  PubMed Central  Google Scholar 

  73. Zhao, Yi, Gang Chen, Wei Zhang, Ning Xu, Jun-Yi Zhu, Jun Jia, Zhi-Jun Sun, Yi-Ning Wang, and Yi-Fang Zhao. 2012. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1α/BNIP3 signaling pathway. Journal of Cellular Physiology 227 (2): 639–648. https://doi.org/10.1002/jcp.22768.

    Article  CAS  PubMed  Google Scholar 

  74. Lindy, Durrant, Rachael L. Metheringham, and Victoria A. Brentville. 2016. Autophagy, citrullination and cancer. Autophagy 12 (6): 1055–1056. https://doi.org/10.1080/15548627.2016.1166326.

    Article  CAS  Google Scholar 

  75. Maurizio, Sorice, Cristina Iannuccelli, Valeria Manganelli, Antonella Capozzi, Cristiano Alessandri, Emanuela Lococo, and Tina Garofalo. 2016. Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies. Rheumatology. 55 (8): 1374–1385.

    Article  CAS  Google Scholar 

  76. Hiroshi, Sasaki, Koji Takayama, Takehiko Matsushita, Kazunari Ishida, Seiji Kubo, Tomoyuki Matsumoto, Norifumi Fujita, Shinya Oka, Masahiro Kurosaka, and Ryosuke Kuroda. 2012. Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis and Rheumatism 64 (6): 1920–1928.

    Article  CAS  Google Scholar 

  77. Musumeci, Giuseppe, Paola Castrogiovanni, Francesca Maria Trovato, Annelie Martina Weinberg, Mohammad K. Al-Wasiyah, Mohammed H. Alqahtani, and Ali Mobasheri. 2015. Biomarkers of chondrocyte apoptosis and autophagy in osteoarthritis. International Journal of Molecular Sciences 16 (9): 20560–20575. https://doi.org/10.3390/ijms160920560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yang, Zhen, Eric L. Matteson, Jörg J. Goronzy, and Cornelia M. Weyand. 2015. T-cell metabolism in autoimmune disease. Arthritis Research & Therapy 17 (1): 29.

    Article  CAS  Google Scholar 

  79. Morel, R. Audo, and B. Combe. 2003. IL-1 but not IL-18 induces osteoprotegerin and TRAIL in rheumatoid arthritis synovial fibroblasts. Arthritis Research & Therapy 5 (3): 1–54.

    Article  Google Scholar 

  80. Fésüs, László, Máté Á. Demény, and Goran Petrovski. 2012. Autophagy shapes inflammation. Antioxidants & Redox Signaling 14 (11): 2233–2243. https://doi.org/10.1089/ars.2010.3485.

    Article  CAS  Google Scholar 

  81. Vojo, Deretic, and Beth Levine. 2009. Autophagy, immunity, and microbial adaptations. Cell Host & Microbe 5 (6): 527–549. https://doi.org/10.1016/j.chom.2009.05.016.

    Article  CAS  Google Scholar 

  82. Martinez-Outschoorn, Ubaldo E., Diana Whitaker-Menezes, Zhao Lin, Neal Flomenberg, Anthony Howell, Richard G. Pestell, Michael P. Lisanti, and Federica Sotgia. 2011. Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle 10 (11): 1784–1793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. de Castro, Celia Peral, Sarah A. Jones, Clíona Ní Cheallaigh, Claire A. Hearnden, Laura Williams, Jan Winter, Ed C. Lavelle, Kingston H.G. Mills, and James Harris. 2012. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. The Journal of Immunology 189 (8): 4144–4153. https://doi.org/10.4049/jimmunol.1201946.

    Article  CAS  Google Scholar 

  84. Wu, Tian-tian, Wei-Min Li, and Yong-Ming Yao. 2016. Interactions between autophagy and inhibitory cytokines. International Journal of Biological Sciences 12 (7): 884–897. https://doi.org/10.7150/ijbs.15194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hiroshi, Sasaki, Koji Takayama, Takehiko Matsushita, Kazunari Ishida, Seiji Kubo, Tomoyuki Matsumoto, Norifumi Fujita, Shinya Oka, Masahiro Kurosaka, and Ryosuke Kuroda. 2012. Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis and Rheumatism 64 (6): 1920–1928. https://doi.org/10.1002/art.34323s.

    Article  Google Scholar 

  86. Lopez de Figueroa, Paloma, Martin K. Lotz, Francisco J. Blanco, and Beatriz Caramés. 2015. Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis & rheumatology 67 (4): 966–976. https://doi.org/10.1002/art.39025.

    Article  CAS  Google Scholar 

  87. Musumeci Giuseppe, Paola Castrogiovanni, Francesca Maria Trovato, Annelie Martina Weinberg, Mohammad K. Al-Wasiyah, Mohammed H. Alqahtani, and Ali Mobasheri. 2015. Biomarkers of chondrocyte apoptosis and autophagy in osteoarthritis. International Journal of Molecular Sciences. 16(9):20560–20575. https://doi.org/10.3390/ijms160920560.

  88. Ruth, Scherz-Shouval, and Zvulun Elazar. 2011. Regulation of autophagy by ROS: physiology and pathology. Trends in Biochemical Sciences 36 (1): 30–38. https://doi.org/10.1016/j.tibs.2010.07.007.

    Article  CAS  Google Scholar 

  89. Hwa, Jung Chang, Seung-Hyun Ro, Jing Cao, Neil Michael Otto, and Do-Hyung Kim. 2010. mTOR regulation of autophagy. Federation of European Biochemical Societies letters 584 (7): 1287–1295. https://doi.org/10.1016/j.febslet.2010.01.017.

    Article  CAS  Google Scholar 

  90. Xu, Ke, Yong-song Cai, She-Min Lu, Xiao-li Li, Liu Lin, Zhong Li, Hui Liu, and Xu. Peng. 2015. Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1. Arthritis Research & Therapy 17 (1): 1–10.

    Article  CAS  Google Scholar 

  91. Zhu, Li, Yu Wu Huaizhou Wang, Zhengwen He, Yanghua Qin, and Qian Shen. 2017. The autophagy level is increased in the synovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators of Inflammation 2017. https://doi.org/10.1155/2017/7623145.

  92. Buckland, Jenny. 2013. Autophagy: a dual role in the life and death of RASFs. Nature Reviews Rheumatology 9 (11): 637–637.

    Article  PubMed  Google Scholar 

  93. Rockel, Jason, and Mohit Kapoor. 2016. Autophagy: controlling cell fate in rheumatic diseases. Nature Reviews Rheumatology 12 (9): 517–531.

    Article  CAS  PubMed  Google Scholar 

  94. Yang, Ru, Yingzi Zhang, Wang Lin, Ji Hu, Jian Wen, Leixi Xue, Mei Tang, Zhichun Liu, and Fu. Jinxiang. 2017. Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis. Oncotarget. 8 (9): 15420–15430. https://doi.org/10.18632/oncotarget.14331.

    Article  PubMed  Google Scholar 

  95. Bao, Jiapeng, Zhonggai Chen, Langhai Xu, Lidong Wu, and Yan Xiong. 2020. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging (Albany NY) 12 (6): 5152–5167. https://doi.org/10.18632/aging.102937.

    Article  CAS  Google Scholar 

  96. Bao, Jiapeng, Zhonggai Chen, Langhai Xu, Lidong Wu, and Yan Xiong. 2020. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging. 12(6):5152–5167. https://doi.org/10.18632/aging.102937.

  97. Schrezenmeier Eva, and Thomas Dörner. 2020. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology. 16:155–166. https://doi.org/10.1038/s41584-020-0372-x.

  98. Ennio, Favalli, Andrea Becciolini, Antonio Carletto, Fabrizio Conti, Giorgio Amato, Enrico Fusaro, and Luca Quartuccio. 2020. Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort. Rheumatology International 40 (2): 263–272.

    Article  CAS  Google Scholar 

  99. Favalli Ennio, Andrea Becciolini, Antonio Carletto, Fabrizio Conti, Giorgio Amato, Enrico Fusaro, and Luca Quartuccio. 2020. Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort. Rheumatology International. 40:263–272. https://doi.org/10.1007/s00296-019-04416-3.

  100. Avdeeva, A.S., Y.P. Rubtsov, D.T. Dyikanov, T.V. Popkova, and E.L. Nasonov. 2020. Regulatory T cells in patients with early untreated rheumatoid arthritis: phenotypic changes in the course of methotrexate treatment. Biochimie. 174: 9–17. https://doi.org/10.1016/j.biochi.2020.03.014.

    Article  CAS  PubMed  Google Scholar 

  101. Avdeeva A. S, Y. P. Rubtsov, D. T. Dyikanov, T. V. Popkova, and E. L. Nasonov. 2020. Regulatory T cells in patients with early untreated rheumatoid arthritis: Phenotypic changes in the course of methotrexate treatment. Biochimie. 174:9–17. https://doi.org/10.1016/j.biochi.2020.03.014.

  102. Papadopoulou, Erofili, Ourania Nicolatou-Galitis, Ioannis Papassotiriou, Helena Linardou, Aikaterini Karagianni, Konstantinos Tsixlakis, Anthi Tarampikou, Kelly Michalakakou, Emmanouil Vardas, and Dimitrios Bafaloukos. 2020. The use of crevicular fluid to assess markers of inflammation and angiogenesis, IL-17 and VEGF, in patients with solid tumors receiving zoledronic acid and/or bevacizumab. Supportive Care in Cancer 28 (1): 177–184.

    Article  PubMed  Google Scholar 

  103. Ma, Zhenzhen, Ruohan Yu, Qiao Zhu, Sun Lin, Leilei Jian, Xinyu Wang, Jinxia Zhao, Changhong Li, and Xiangyuan Liu. 2020. CXCL16/CXCR6 axis promotes bleomycin-induced fibrotic process in MRC-5 cells via the PI3K/AKT/FOXO3a pathway. International Immunopharmacology 81: 106035. https://doi.org/10.1016/j.intimp.2019.106035.

    Article  CAS  PubMed  Google Scholar 

  104. MacKeigan, Jeffrey Paul, Katie Renee Martin, Megan Lynne Goodall, Stephen T. Gately, and Tong Wang.2020. Autophagy inhibitors. U.S. Patent 10,544,100.

  105. Klinkhoff, Alice. 2004. Biological agents for rheumatoid arthritis. Drugs. 64 (12): 1267–1283.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Tapan Behl or Simona Bungau.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chadha, S., Behl, T., Bungau, S. et al. Focus on the Multimodal Role of Autophagy in Rheumatoid Arthritis. Inflammation 44, 1–12 (2021). https://doi.org/10.1007/s10753-020-01324-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01324-8

KEY WORDS

Navigation