Pathophysiology of iron and hepcidin metabolism: research perspectives in rheumatolog
https://doi.org/10.47360/1995-4484-2022-519-525
Abstract
Despite advances in the study of iron metabolism, anemia of chronic inflammation (AI) and iron deficiency remain major global health problems. In immunoinflammatory rheumatic diseases (RD), the most common variants are iron deficiency anemia (IDA) as the most common type of anemia, and AI, which itself can aggravate the course of the underlying disease due to tissue iron overload, additional activation and maintenance of inflammation activity. In recent years, the diagnostic and therapeutic role of hepcidin as a key regulator of iron metabolism has been widely discussed.
The study of the ways of regulation and synthesis of hepcidin in immuno-inflammatory RD may be of great importance for identifying the pathogenetic mechanisms underlying the formation of resistance to therapy, as well as for the appearance of severe concomitant pathology in patients that makes it difficult to prescribe adequate therapy. The most interesting from the perspective of further study are the interleukin 6 – JAK2 – STAT3 axis and chronic hypoxia, which occurs in such chronic conditions as cardiovascular pathology, chronic kidney disease, interstitial lung damage, etc.
About the Authors
A. M. Lila
V.A. Nasonova Research Institute of Rheumatology;
Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation
Russian Federation
Russian Federation
115522, Moscow, Kashirskoye Highway, 34A; 125993, Moscow, Barrikadnaya str., 2/1, building 1
E. A. Galushko
V.A. Nasonova Research Institute of Rheumatology
Russian Federation
Russian Federation
115522, Moscow, Kashirskoye Highway, 34A
A. S. Semashko
V.A. Nasonova Research Institute of Rheumatology
Russian Federation
Russian Federation
115522, Moscow, Kashirskoye Highway, 34A
References
1. Roemhild K, von Maltzahn F, Weiskirchen R, Knüchel R, von Stillfried S, Lammers T. Iron metabolism: Pathophysiology and pharmacology. Trends Pharmacol Sci. 2021;42(8):640–656. doi: 10.1016/ j.tips.2021.05.001
2. Rauf A, Shariati MA, Khalil AA, Bawazeer S, Heydari M, Plygun S, et al. Hepcidin, an overview of biochemical and clini - cal properties. Steroids. 2020;160:108661. doi: 10.1016/ j.steroids.2020.108661
3. Nasonov EL, Olyunin YuA, Lila AM. Rheumatoid arthritis: The problems of remission and therapy resistance. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2018;56(3): 263–271 (In Russ.)]. doi: 10.14412/1995-4484-2018-263-271
4. Nasonov EL, Lila AM. Janus kinase inhibitors in immuno-inflammatory rheumatic diseases: New opportunities and prospects. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2019;57(1):8–16 (In Russ.)]. doi: 10.14412/1995-4484-2019-8-16
5. Galushko EA, Gordeev AV, Matyanova EV, Olyunin YA, Nasonov EL. Difficultto-treat rheumatoid arthritis in real clinical practice. Preliminary results. Terapevticheskii arkhiv. 2022;94(5):660–665 (In Russ.)]. doi: 10.26442/00403660.2022.05.201489
6. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40–50. doi: 10.1182/blood-2018-06-856500
7. Mazurov VI, Lila AM. Features of anemic syndrome in patients with rheumatoid arthritis and systemic lupus erythematosus. Medical Academic Journal. 2001;1:58 (In Russ.).
8. Gordeev AV, Galushko EA, Savushkina NM, Demidova NV, Semashko AS. Assessing the multimorbid profile (CIRS) in rheumatoid arthritis. First results. Modern Rheumatology Journal. 2019;13(3):10–16 (In Russ.). doi: 10.14412/1996-7012-2019-3-10-16
9. Weiss G. Anemia of chronic disorders: New diagnostic tools and new treatment strategies. Semin Hematol. 2015;52(4):313–320. doi: 10.1053/j.seminhematol.2015.07.004
10. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, et al.; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50(4):1051–1065. doi: 10.1002/art.20159
11. Galushko EA, Belenkiy DA. Modern aspects of diagnosis and treatment of anemia in rheumatoid arthritis patients. Nauchno- Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2012;50(5):98–105 (In Russ.). doi: 10.14412/1995-4484-2012-1189
12. Lanser L, Fuchs D, Kurz K, Weiss G. Physiology and inflammation driven pathophysiology of iron homeostasis-mechanistic insights into anemia of inflammation and its treatment. Nutrients. 2021;13(11):3732. doi: 10.3390/nu13113732
13. Nasonov EL, Lila AM. Inhibition of interleukin 6 in immune inflammatory rheumatic diseases: Achievements, prospects, and hopes. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2017;55(6):590–599 (In Russ.) doi: 10.14412/1995-4484-2017-590-599
14. Grillo AS, SantaMaria AM, Kafina MD, Cioffi AG, Huston NC, Han M, et al. Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science. 2017;356(6338):608–616. doi: 10.1126/science.aah3862
15. Petzer V, Theurl I, Weiss G. Established and emerging concepts to treat imbalances of iron homeostasis in inflammatory diseases. Pharmaceuticals (Basel). 2018;11(4):135. doi: 10.3390/ph11040135
16. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10:9–17.
17. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93:1721-1741.
18. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117(7):1933–1939. doi: 10.1172/JCI31342
19. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–7819. doi: 10.1074/jbc.M008923200
20. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168:344–361. doi: 10.1016/ j.cell.2016.12.034
21. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093. doi: 10.1126/science.1104742
22. Fillebeen C, Wilkinson N, Charlebois E, Katsarou A, Wagner J, Pantopoulos K. Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling. Blood. 2018;132(17):1829–1841. doi: 10.1182/blood-2018- 03-841197
23. Canali S, Zumbrennen-Bullough KB, Core AB, Wang CY, Nairz M, Bouley R, et al. Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood. 2017;129(4):405–414. doi: 10.1182/blood-2016-06-721571
24. Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, et al. Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica. 2012;97(6):827– 834. doi: 10.3324/haematol.2011.056119
25. Taylor M, Qu A, Anderson ER, Matsubara T, Martin A, Gonzalez FJ, et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140(7):2044–2055. doi: 10.1053/ j.gastro.2011.03.007
26. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832–1843. doi: 10.1056/NEJMra1401038
27. Sankaran VG, Weiss MJ. Anemia: Progress in molecular mechanisms and therapies. Nat Med. 2015;21(3):221-230. doi: 10.1038/ nm.3814
28. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109(1):353–358. doi: 10.1182/blood-2006-07-033969
29. Cavezzi A, Menicagli R, Troiani E, Corrao S. COVID-19, cation dysmetabolism, sialic acid, CD147, ACE2, viroporins, hepcidin and ferroptosis: A possible unifying hypothesis. F1000Res. 2022;11:102. doi: 10.12688/f1000research.108667.2
Review
For citations:
Lila A.M., Galushko E.A., Semashko A.S. Pathophysiology of iron and hepcidin metabolism: research perspectives in rheumatolog. Rheumatology Science and Practice. 2022;60(5):519-525. (In Russ.) https://doi.org/10.47360/1995-4484-2022-519-525
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