Elisha AKANBONG, ALPARSLAN KADİR DEVRİM, Ali ŞENOL, Tuba DEVRİM

COMPREHENDING COVID-19: IMMUNOPATHOGENIC MECHANISMS OF CYTOKINE ACTION

Cytokine release syndrome (CRS) or cytokine storm is as a result of the excess production of pro-inflammatory cytokines which is due to the disproportionate response of the immune system which can be instigated by SARS-CoV-2. COVID-19 which is caused by SARSCoV- 2 has a correlation with cytokines. SARSCoV- 2 instigates the production of IL-1 by ubiquitous macrophages and mast cells. IL-1 tends to influence the production of IL-6 and TNF-α. The progression of COVID-19 severity influences the level of certain cytokines such as IL-6. IL-6 is the cytokine chiefly responsible for the occurrence of CRS. CRS is the cause of COVID-19-related complications and the main cause of COVID-19-related deaths. Despite the data reported in the literature so far, the relationship between SARS-CoV-2 and cytokines has not been fully elucidated. The aim of the present review is to examine the relationship in question. Targeting cytokines during COVID-19 treatment has the potential to increase patient survival and reduce COVID-19-related deaths. It is concluded that focusing on the mechanisms of cytokine release and the effects of released cytokines, especially examining the effects on T lymphocytes and IFN-γ production in COVID-19 disease, may help reduce the lethal effects of the disease.

COVID-19'U ANLAMAK: SİTOKİN ETKİSİNİN İMMÜNOPATOJENİK MEKANİZMALARI

Sitokin salınım sendromu (SSS) veya sitokin fırtınası, SARS-CoV-2 tarafından başlatılabilen, bağışıklık sisteminin orantısız tepkisinden kaynaklanan proinflamatuar sitokinlerin aşırı üretiminin bir sonucudur. SARS-CoV-2'nin neden olduğu COVID-19, sitokinlerle korelasyon göstermektedir. SARS-CoV-2, yaygın dağılım gösteren makrofajlar ve mast hücreleri sayesinde IL-1 üretimini tetiklemektedir. IL-1 ise, IL-6 ve TNF-α üretimlerini etkileme eğilimindedir. COVID-19 şiddetinin ilerlemesi, IL-6 gibi bazı sitokin düzeylerini etkiler. IL-6, SSS oluşumundan başlıca sorumlu olan sitokindir. SSS, COVID-19 ile ilgili komplikasyonların ve COVID-19 ile ilişkili ölümlerin ana nedenidir. Bu zamana kadar literatürde bildirilmiş verilere rağmen, SARS-CoV-2 ve sitokinler arasındaki ilişki tam olarak aydınlatılmış değildir. Bu derleme ile söz konusu ilişkinin irdelenmesi amaçlamıştır. COVID-19 tedavisi sırasında sitokinlerin hedeflenmesi, hastaların hayatta kalma oranlarını artırma ve COVID-19 ile ilişkili ölümleri azaltma potansiyelini taşımaktadır. COVID-19 hastalığında, sitokin salınım mekanizmalarına ve salınan sitokinlerin etkilerine odaklanılmasının, özellikle T lenfositler üzerindeki etkilerinin ve IFN-γ üretiminin irdelenmesinin, hastalığın ölümcül etkilerini azaltmaya yardımcı olabileceği düşünülmektedir.

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1. Li X, Geng M, Peng Y, Meng L. Lu Sh. Mol immune Pathog diagnosis COVID-19, J Pharm Anal. 2020; 10(2):102–8.

2. Darif D, Hammi I, Kihel A, El Idrissi Saik I, Guessous F, Akarid K. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong? Microb Pathog [Internet]. 2021; 153:104799. Available from: https://www.sciencedirect.com/science/article/ pii/S0882401021000711

3. Kunnumakkara AB, Rana V, Parama D, Banik K, Girisa S, Sahu H et al. COVID-19, cytokines, inflammation, and spices: How are they related?. Life sciences. 2021 Feb 16:119201. https://www. sciencedirect.com/science/article/pii/S0024320521001867

4. Karabacak P, Kırdemir P. COVID-19 hastalarında akut solunum sıkıntısı sendromu yönetimi. Med J SDU. 2021 (özel sayı- 1): 51-56. DOI: 10.17343/sdutfd.901174.

5. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. The lancet. 2020; 395(10223): 514-23. Available from: https://www.sciencedirect.com/science/article/pii/ S0140673620301549

6. Dinarello CA. Impact of basic research on tomorrow’s medicine. Chest. 2000; 118(2): 503–8.

7. dos Santos G, Delay L, Yaksh TL, Corr M. Neuraxial Cytokines in Pain States. Front Immunol [Internet]. 2020; 10:3061. Available from: https://www.frontiersin.org/article/10.3389/fimmu. 2019.03061

8. Fares J, Cordero A, Kanojia D, Lesniak MS. The Network of Cytokines in Brain Metastases. Cancers (Basel). 2021; 13(1): 142.

9. Chauhan P, Nair A, Patidar A, Dandapat J, Sarkar A, Saha B. A primer on cytokines. Cytokine. 2021 Feb; 155458.

10. Devrim T, Ekici H, Devrim AK, Sozmen M, Senol A, Bozkurt KM, Duru O. Late effects of cutaneous 3-methylcholanthrene exposure on DNA damage-related pleiotropic growth factors and oxidative stress markers in mice. Bratisl Med J, 2020; 121(5): 325-330.

11. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL et al. Cytokines in clinical cancer immunotherapy. British journal of cancer. 2019; 120(1): 6-15.

12. Devrim T, Ataç F, Devrim AK, Balcı M. The concomitant use of USP28 and p53 to predict the progression of urothelial carcinoma of the bladder. Pathol Pract. 2020; 216(1): 152774.

13. Simpson S, Kaislasuo J, Guller S, Pal L. Thermal stability of cytokines: A review. Cytokine. 2020; 125:154829.

14. Katze M. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012; 76(1): 16–32.

15. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020; 5(1): 1–17.

16. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. Int J Cell Biol. 2016; 2016: 9259646.

17. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M et al. Cytokine release syndrome. Journal for immunotherapy of cancer. 2018; 6(1):1-4.

18. Tang X, Wu C, Li X, Song Y, Yao X, Wu X et al. On the origin and continuing evolution of SARS-CoV-2. National Science Review. 2020; 7(6): 1012-23.

19. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect. 2020; 80(6): 607-613.

20. Mahmud-Al-Rafat A, Asim MM, Taylor-Robinson AW, Majumder A, Muktadir A, Muktadir H et al. A combinational approach to restore cytokine balance and to inhibit virus growth may promote patient recovery in severe COVID-19 cases. Cytokine, 2020; 15:155228.

21. Sallenave J-M, Guillot L. Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in Covid-19: key therapeutic targets? Front Immunol. 2020;11.

22. Conti P, Caraffa A, Gallenga CE, Ross R, Kritas SK, Frydas I et al. Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: a promising inhibitory strategy. J Biol Regul Homeost Agents. 2020; 34(6): 1971-5.

23. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet. 2020; 395(10223): 497-506.

24. Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A. Role of the IL-6 classic-and trans-signaling pathways in corneal sterile inflammation and wound healing. Invest Ophthalmol Vis Sci. 2011; 52(12): 8549–57.

25. Goncalves C-A, Sesterheim P. Serum amyloid A protein has been undervalued as a biomarker of COVID-19. Diabetes Metab Res Rev. 2020; 26:e3376.

26. Mosquera‐Sulbaran JA, Pedreañez A, Carrero Y, Callejas D. C‐reactive protein as an effector molecule in Covid‐19 pathogenesis. Rev Med Virol. 2021; e2221.

27. Chatterjee SK, Saha S, Munoz MNM. Molecular Pathogenesis, Immunopathogenesis and Novel Therapeutic Strategy Against COVID-19. Front Mol Biosci [Internet]. 2020; 7:196. Available from: https://www.frontiersin.org/article/10.3389/ fmolb.2020.00196

28. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC et al. Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy. 2020; 75(7): 1564-81.

29. Behrens EM, Koretzky GA. Cytokine storm syndrome: Looking toward the precision medicine era. Arthritis Rheumatol. 2017; 69(6): 1135–43.

30. Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020; 53: 25–32.

31. Numbers K, Brodaty H. The effects of the COVID-19 pandemic on people with dementia. Nat Rev Neurol. 2021; 1–2.

32. Chen G, Wu DI, Guo W, Cao Y, Huang D, Wang H et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of clinical investigation. 2020; 130(5): 2620-9.

33. Wang F, Hou H, Luo Y, Tang G, Wu S, Huang M et al. The laboratory tests and host immunity of COVID-19 patients with different severity of illness. JCI insight. 2020; 5(10): e137799.

34. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020; 369(6504): 718-24.

35. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerging microbes & infections. 2020; 9(1): 1123-30.

36. Gao Y, Li T, Han M, Li X, Wu D, Xu Y et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID‐19. Journal of medical virology. 2020; 92(7): 791-6.

37. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46(5): 846–8.

38. Liu Y, Zhang C, Huang F, Yang Y, Wang F, Yuan J et al. Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury. National Science Review. 2020; 7(6): 1003-11.

39. Ryzhakov G, Lai CC, Blazek K, To K, Hussell T, Udalova I. IL- 17 Boosts Proinflammatory Outcome of Antiviral Response in Human Cells. J Immunol [Internet]. 2011; 187(10): 5357–5362. Available from: http://www.jimmunol.org/content/187/10/5357. abstract

40. Hou W, Jin Y-H, Kang HS, Kim BS. Interleukin-6 (IL-6) and IL- 17 Synergistically Promote Viral Persistence by Inhibiting Cellular Apoptosis and Cytotoxic T Cell Function. Perlman S, editor. J Virol [Internet]. 2014; 88(15): 8479 LP – 8489. Available from: http://jvi.asm.org/content/88/15/8479.abstract

41. Yang AP, Liu J ping, Tao W qiang, Li H ming. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol [Internet]. 2020; 84: 106504. Available from: https://doi.org/10.1016/j.intimp.2020.106504

42. Feng X, Li S, Sun Q, Zhu J, Chen B, Xiong M, et al. Immune- inflammatory parameters in COVID-19 cases: A systematic review and meta-analysis. Front Med. 2020; 7: 1–14.

43. Simadibrata DM, Pandhita BAW, Ananta ME, Tango T. Platelet- to-lymphocyte ratio, a novel biomarker to predict the severity of COVID-19 patients: A systematic review and meta- analysis. J Intensive Care Soc. 2020; DOI: https://doi. org/10.1177/1751143720969587

44. Kong J, Wang T, Di Z, Shi B, Yu X, Huang C, et al. Analysis of hematological indexes of COVID-19 patients from fever clinics in Suzhou, China. Int J Lab Hematol. 2020; 42(5): e204–6.

45. Xu X, Han M, Li T, Sun W, Wang D, Fu B et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences. 2020; 117(20): 10970- 5. Available from: http://www.pnas.org/content/117/20/10970. abstract

46. Ye Q, Wang B, Mao J. Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information. J Infect. 2020;(January).

47. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: a descriptive study. Lancet, 2020; 395 (10223): 507-513.