Gas6/TAM Axis Involvement in Modulating Inflammation and Fibrosis in COVID-19 Patients

Abstract

Gas6 (growth arrest-specific gene 6) is a widely expressed vitamin K-dependent protein that is involved in many biological processes such as homeostatic regulation, inflammation and repair/fibrotic processes. It is known that it is the main ligand of TAMs, a tyrosine kinase receptor family of three members, namely MerTK, Tyro-3 and Axl, for which it displays the highest affinity. Gas6/TAM axis activation is known to be involved in modulating inflammatory responses as well as fibrotic evolution in many different pathological conditions. Due to the rapidly evolving COVID-19 pandemic, this review will focus on Gas6/TAM axis activation in SARS-CoV-2 infection, where de-regulated inflammatory responses and fibrosis represent a relevant feature of severe disease manifestation. Furthermore, this review will highlight the most recent scientific evidence supporting an unsuspected role of Axl as a SARS-CoV-2 infection driver, and the potential therapeutic advantages of the use of existing Axl inhibitors in COVID-19 management. From a physiological point of view, the Gas6/TAM axis plays a dual role, fostering the tissue repair processes or leading to organ damage and loss of function, depending on the prevalence of its anti-inflammatory or profibrotic properties. This review makes a strong case for further research focusing on the Gas6/TAM axis as a pharmacological target to manage different disease conditions, such as chronic fibrosis or COVID-19.

Plasma proteomic associates of infection mortality in UK Biobank

“…However, the broader link between Mertk and infection has been made in a variety of murine models and human observational studies, giving further credence to our finding. (29)(30)(31)(32)(33)(34)(35) This supports a focus on MERTK and its partners in a search for therapeutics to reduce risk of fatal infection, in addition to potential roles as biomarkers.…”

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters

“…Such experimental evidence supports the reliability of basal Gas6 levels in the early stratification of COVID-19 patients according to their expected negative evolution; on the other hand, studies regarding the predictive ability of the Gas6/TAM axis toward long-term sequelae are still warranted [ 131 ], and could represent an interesting starting point to implement currently available disease evolution prediction models. Finally, it should be noted that according to recent in vitro and in vivo evidence highlighting the possible role of Axl in SARS-CoV-2 infection, different studies are ongoing with the aim to repurpose Axl inhibitors as potential anti-COVID-19 drugs [ 131 , 150 , 151 ], thus supporting the interest in the implementation of Gas6/TAM screening in clinical practice.…”

“…Furthermore, it should be considered that many of these biomarkers, and especially those most strictly related to cytokine storm, could also be valuable tools to monitor therapeutic responses (i.e., CRP and IL6 after 7 days of hospitalization) and promising direct (i.e., IL6) or indirect (i.e., D-dimer) pharmacological targets in selected patients. Lastly, it is noteworthy that the continuous biotechnological progresses in the field of COVID-19 biomarkers discovery have also led to new and promising findings in terms of possible therapeutic approaches, as demonstrated by the anti-inflammatory and anti-viral activity of heparin [ 198 , 199 , 200 ], by the ability of IL6 and other IL- and cytokine-signaling inhibitors to improve the disease course [ 101 , 102 , 109 , 110 , 201 , 202 , 203 , 204 , 205 ] and by the promising antiviral effects of the already existing Gas6/TAM axis inhibitors [ 131 , 150 , 151 ]. Moreover, several studies are currently focused on both drug repurposing and new drug development, thus representing new potential options to directly or indirectly target several key mediators of COVID-19 pathogenesis [ 203 , 206 , 207 , 208 ].…”

“…Gas6 biological activities depend on its binding to one of the three members of a family of tyrosine kinase receptors, collectively named TAM (for Tyro-3, Axl, MerTK), which in turn activates different intracellular signaling pathways (i.e., the p38/MAPK, the ERK1/2, the JAK/STAT, and the PI3K/Akt pathways) [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ].…”

“…Due to its widely recognized role in immunomodulation, the Gas6/TAM axis has also been investigated in the context of COVID-19, especially considering that one of the distinctive hallmarks of the severe disease is represented by an hyperinflammatory response, accountable for both disease severity and long-term sequelae [ 3 , 14 , 131 , 139 , 140 , 141 , 142 ].…”