The role of FLIP as a moonlighting protein is becoming progressively evident since this protein is often involved in various processes correlated to aberrant immunological responses independently from its function as master anti-apoptotic regulator. It has been uncovered that FLIP drives the acquisition of immunosuppression and inflammation-associated pathways in myeloid cells. The clinical picture raised during SARSCoV- 2 pandemic has given the possibility to deeply investigate FLIP involvement in releasing a systemic cytokine storm, also linked to a chronic inflammatory syndrome associated with immune suppression and cancer progression. Indeed, a FLIP/STAT3 axis orchestrates an aberrant inflammatory program in myeloid cells of COVID-19 patients and SARS-CoV-2 infected hACE2 transgenic mice. Moreover, the same activated FLIP/STAT3 axis was confirmed in a chimeric vFLIP mouse model, where vFLIP overexpression was restricted exclusively in myeloid cells by using a tissue-specific CRE-driver (e.g., LysMCre mice), validating this model as a feasible platform to study the late phase of COVID-19 disease. The STAT3 pro-inflammatory pathway triggered by the aberrant expression of FLIP in myeloid cells well correlates to the outcome of the cytokine release syndrome (CRS) that is the latest and most severe phase in COVID-19 disease confirming FLIP-mediated myeloid reprogramming as a cornerstone of systemic immune disorders.

c-FLIP (Cellular FLICE [FADD-like IL-1β-converting enzyme]-inhibitory protein), CRS (Cytokine Release Syndrome), COVID-19, Inflammation, Myeloid cells