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Table of Contents
Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 247-248

Renin-angiotensin axis as a trigger for immune dysregulation in COVID-19

Department of Internal Medicine, Rangadore Memorial Hospital, Bengaluru, Karnataka, India

Date of Submission23-Jul-2020
Date of Acceptance04-Sep-2020
Date of Web Publication5-Jan-2021

Correspondence Address:
Suma Nagesh
Consultant Physician, Rangadore Memorial Hospital, 1st Cross Road, Shankarapuram, Basavanagudi, Bengaluru 560 004, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCSR.JCSR_62_20

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How to cite this article:
Rao SN, Nagesh S. Renin-angiotensin axis as a trigger for immune dysregulation in COVID-19. J Clin Sci Res 2020;9:247-8

How to cite this URL:
Rao SN, Nagesh S. Renin-angiotensin axis as a trigger for immune dysregulation in COVID-19. J Clin Sci Res [serial online] 2020 [cited 2021 Jan 20];9:247-8. Available from: https://www.jcsr.co.in/text.asp?2020/9/4/247/306195

We read with interest the review article titled “Immune dysregulation in COVID-19 and its therapeutic implications” by Praveen et al.[1] We commend the authors on their ability to distil the intricacies of a complex immunopathogenesis into categorised and understandable terms. Though well written, we would like to address three key points and hope our contribution helps improve our understanding of the pathogenesis of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) infection. The review article seems to speak along the terms of a general inflammatory system that would lead to a cytokine storm. While this can occur in the setting of any virus, severe COVID-19 seems to be particularly prone to produce this staggering response to infection.

The first point central to the discussion is the deficient CD8/NK cell pathway leading to an exaggerated macrophage response causing a macrophage activation syndrome (MAS). This is however the pathway proposed for MAS in the setting of rheumatologic pathways and is not unique to SARS CoV2. The NK cell pathway deficiency is known to be potentiated by interleukin-6 (IL-6).[2] The second point is the critical role played by IL-6 in the potentiation of the cytokine storm. This directly ties in with the aforementioned pathway. An important molecule, as mentioned in the article, is ADAM17 that acts as a “sheddase” for IL-6, thus magnifying its effects. The final point specific to the pathogenesis, as mentioned is the downregulation of ACE2 receptors by SARS CoV2. We believe that these three attributes might play a pivotal role in the pathogenesis of COVID-19.

The renin-angiotensin system (RAS) is well known to have immunomodulatory effects. The utilization of ACE2 receptors and its downregulation by SARS CoV2 potentiates an Angiotensin II-based response. A study on the SARS CoV virus showed that the spike protein of the virus led to ADAM17 activation, which caused ACE2 downregulation by clipping.[3] This could potentially drive a positive feedback loop leading to massive inflammation and cytokine storm. While the reduced ACE2/ACE activity mediated pro-inflammatory response helps release IL-6, the ADAM17 potentiates this by simultaneously reducing ACE2 and worsening the IL-6 release. ADAM17, through its tumour necrosis factor-alpha (TNF-α) converting enzyme (TACE) activity, cleaves transmembrane TNF-α to release it into the milieu.

We would like to reason that the crux of the pathogenesis lies in the dysregulated RAS axis. The dysregulation of the immune response would be a result of the above. A positive feedback loop in the RAS axis would explain the rapid clinical deterioration of patients. IL-6 overproduction would lead to a hyper-immune response and a cytokine storm. This would also downregulate the CD8/NK cell axis. TACE activation would then help recruit and maintain a sustained macrophage response through TNF-α release leading to MAS. This theory is backed by animal studies which have suggested a protective role of ADAM17 inhibitors.[4]

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Conflicts of interest

There are no conflicts of interest.

  References Top

Praveen T, Desai D, Soneja M, Wig N. Immune dysregulation in COVID-19 and its therapeutic implications. J Clin Sci Res 2020;9:37.  Back to cited text no. 1
  [Full text]  
Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol 2015;67:3037-46.  Back to cited text no. 2
Haga S, Yamamoto N, Nakai-Murakami C, Osawa Y, Tokunaga K, Sata T, et al. Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry. Proc Natl Acad Sci U S A 2008;105:7809-14.  Back to cited text no. 3
Palau V, Riera M, Soler MJ. ADAM17 inhibition may exert a protective effect on COVID-19. Nephrol Dial Transplant 2020;35:1071-2.  Back to cited text no. 4


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