Figure 2.

NOTCH signaling induces IL-6 in a positive-feedback loop. NOTCH signaling promotes the production of inflammatory cytokines including IL-6. In turn, IL-6 increases the expression of NOTCH ligands (such as Dll1 and Dll4), which can further amplify NOTCH signaling. This NOTCH : IL-6 positive-feedback loop can promote innate immune cell and adaptive immune T cell activation together with further amplified inflammatory cytokine elaboration. When these processes are highly active without sufficient downregulation in a resolution phase, they can cause inflammatory tissue damage and continued cycles of IL-6 and NOTCH upregulation and activation. While monoclonal antibodies (mAbs) that block IL-6 or its receptor represent promising therapeutic modalities, GSIs block NOTCH signaling as candidate drugs in clinical trials for other diseases, and these latter compounds could be contemplated when severe COVID-19 may be unresponsive to other therapies. In sum, it is suggested that targeting the positive feedback loop between NOTCH and IL-6 could be a potential therapeutic strategy that may have application against COVID-19.