Fig. 2 | Signal Transduction and Targeted Therapy

Fig. 2

From: Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Fig. 2

Hypothetical mechanism by SARS-CoV-2 in establishing an inflammatory feedback loop between IL-6 and angiotensin II. Cytokine IL-6 has been found increased in COVID-19 patients, thus suggesting a direct role of SARS-CoV-2 in a massive cytokine release. IL-6 is able to activate a soluble form of IL-6 receptor interacting with gp130, thereby promoting the downstream activation of JAK/STAT signaling, and thely production of IL-6. Moreover, SARS-CoV-2 has been directly related with the occurrence of cardiovascular implications, such as coronary atherosclerosis, inflammation in the vascular system and diffuse microangiopathy with thrombosis. Synthesis and secretion of IL-6 are directly implicated in cardiovascular damages. Indeed, IL-6 production is also induced by angiotensin II in AT1/JAK/STAT-dependent manner. As observed in SARS-CoV, also SARS-CoV-2 may be hypothesized to downregulate ACE2 expression, thus resulting in over-production of angiotensin II by the related enzyme ACE. In turn, increased angiotensin II enhances IL-6 production via JAK/STAT pathway, thus establishing a positive inflammatory feedback loop, ultimately resulting in the exacerbation of vascular and lung injuries. Moreover, the angiotensin II/AT1 receptor axis activates ADAM17 that cleavages and inactivates ACE2, enhancing angiotensin II retention. In addition, ADAM17 induction has been found to process the membrane form of IL-6Rα to the soluble form (sIL-6Rα), followed by the gp130-mediated activation of STAT3 via the sIL-6Rα-IL-6 complex in a variety of IL-6Rα-negative non-immune cells. The IL-6 amplifier promotes the production and secretion of several pro-inflammatory cytokines and chemokines, such as IL-6, sustaining the IL-6 amplifier-driven positive feedback. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IL-6, interleukin 6; ACE2, angiotensin-converting enzyme 2; AT1, angiotensin II receptor type 1; JAK, Janus Kinase; STAT, Signal Transducer and Activator of Transcription; ADAM17, A Disintegrin And Metalloproteinase domain-containing protein 17

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