Due to its immunomodulatory role, as well as its involvement in the modulation of inflammation and subsequent fibrotic evolution, the Gas6/TAM axis is emerging as an interesting research item in the context of the ongoing COVID-19 pandemic, caused by SARS-CoV-2. This new viral agent is a positive, enveloped, single-stranded RNA virus, with high genetic similarity with both SARS-CoV and MERS-CoV, two epidemic coronaviruses responsible for two other severe pneumonia outbreaks in 2002 and 2012, respectively [58,59,60].

SARS-CoV-2-positive patients show different clinical manifestations, ranging from asymptomatic forms or mild flu-like presentation to severe interstitial pneumonia, acute respiratory distress syndrome (ARDS) and severe multiorgan failure, leading, in the most severe cases, to death [58,61,62,63,64,65]. A distinctive hallmark of severe COVID-19 manifestations is the aberrant immune response following pathogen recognition, leading to uncontrolled production and release of proinflammatory mediators, accounting for the so-called “cytokine storm”, which appears to have peculiar characteristics in COVID-19 compared to what is observed in other non-COVID-19-related manifestations [66,67]. Such hyperinflammatory response correlates with disease severity and is characterized by an increase in proinflammatory cytokines, both in the bloodstream and in the bronco–alveolar lavage fluids [61,65,66,67,68,69].

Many studies have reported that a great percentage of patients surviving COVID-19 infection still display respiratory impairment even after discharge, resulting in a reduction in some key physiological parameters such as total lung capacity, forced vital capacity and forced expiratory volume as well as gas transfer ability, finally resulting in a long-term progressive and irreversible deterioration of lung function [61,62,70,71,72,73,74,75].

Consistently, recent studies showed that a large proportion of severe COVID-19 survivors develop fibrotic changes in the lung persisting for months after discharge, especially in elderly, male and mechanically ventilated patients, displaying high levels of inflammation markers (i.e., C-reactive protein (CRP), IL-6, lactate dehydrogenase (LDH), D-dimer). Furthermore, it has been observed that the degree of inflammation and the extent of lung tissue damage correlate with the degree of lung fibrosis, supporting the observed high prevalence of such complication in the most critical patients compared to those experiencing only a mild or moderate form of COVID-19 [70,72,75,76].

Considering its effect in modulating host immune responses, the Gas6/TAM axis has also gained attention in the context of COVID-19 studies, showing a direct correlation between plasma Gas6 levels and disease severity [77,78,79,80]. Table 1 and Table 2 summarize the most relevant papers investigating Gas6 and TAM receptor involvement in SARS-CoV-2 infection and subsequent disease.

The first work theorizing a correlation between the Gas6/TAM axis and COVID-19 was a review by Tutusaus and colleagues, who suggested the TAM pathway involvement at different stages of SARS-CoV-2 infection, mainly focusing on viral mimicry and immunothrombosis, which is often observed as a complication in severe patients experiencing ARDS [92]. Since the publication of that work, many research groups focused their attention on this signaling pathway activation in COVID-19 to disclose the existing correlations between the Gas6/TAM axis and disease evolution. To date, most of the available studies in the literature on this topic date back to the first wave of the pandemic and show some important limits. The most significant limitations of these studies are represented by the wide difference in disease severity at admission and the hospital management of patients, as no clear therapeutic guidelines were available at that time, so, in many cases, information about pharmacological treatment is missing in published reports.

In their study, Morales and coworkers evaluated plasma Gas6 and sTAM expression at admission to emergency care units and observed a direct correlation between basal Gas6 and sAxl levels and disease severity [80]. Similar results were obtained also by Huckriede and colleagues, who studied a cohort of patients admitted to the ICU with severe disease, observing that plasma Gas6 levels were significantly higher in nonsurvivors compared to patients recovering from the disease, allowing good discrimination of patients who will develop irreversible acute lung injury. On the other hand, they did not find any correlation between sAxl levels and organ damage, further highlighting the importance of Gas6 in predicting disease evolution [79]. De Bruin’s research group also obtained similar results in a cohort of patients admitted to the ICU and general wards, where a correlation between plasma Gas6 levels and negative disease evolution was observed [78].

It is important to note that almost all reports in the literature about the involvement of the Gas6/TAM axis in COVID-19 focus on the adult population. To date, only one study [81] evaluated this issue in pediatric patients, highlighting that, in contrast to what was observed in adults, both Gas6 and MerTK levels are lower in infected individuals than in healthy individuals, an observation that further supports the different disease evolution according to the age of the infected patients.

Even if the majority of the research papers are focused on the Gas6/TAM axis involvement in COVID-19, interesting results also come from in vitro research. Since the first decade of this century, different studies demonstrated, in vitro, that TAM receptors and their ligands, by acting as a bridge with PtdSer, could promote different enveloped virus infections (i.e., filovirus such as Ebola, and flaviviruses such as Dengue and West Nile) [22,25,92,98]. In particular, the Axl role in lung viral infections has also been studied in a murine model, where it has been demonstrated that its inhibition by monoclonal antibodies locally enhanced innate and adaptive immunity, suggesting Axl-targeted inhibition as an interesting clinical approach to treat viral lung diseases [99]. It is noteworthy that, according to available in vitro and in vivo evidence, Axl is not indispensable for enveloped virus entry, but might reasonably act as a “facilitator” in some cell types rather than others [22].

According to such evidence, Axl has also been investigated in the context of COVID-19 and in vitro results have highlighted an unsuspected role of Axl in the SARS-CoV-2 infection process, even if its exact mode of action has not yet been clarified. In particular, some reports demonstrated that the Axl receptor can specifically interact with the N-terminal domain of SARS-CoV-2 spike protein in an ACE2-independent manner, thus representing a potential alternative receptor for viral entry in pulmonary and bronchial epithelial cells, where Axl and ACE2 receptors are not co-expressed. These in vitro studies highlighted that knocking down Axl or its addition in the soluble recombinant form to cell culture is effective in reducing the viral infection of pulmonary epithelial cells, while its biological ligands (Gas6 and protein S) do not bind to SARS-CoV-2 [82,93]. According to this evidence, Axl may be involved in the viral endocytosis mechanism by interacting with virion-associated PtdSer residues [83,94]. Consistently, the inhibition of the intracellular Axl signaling pathway with bemcentinib reduced receptor-mediated viral internalization and new virions production in a dose-dependent manner [83].

This ability of SARS-CoV-2 to exploit different cellular receptors to infect host cells not only offers a reasonable explanation for its high infectivity and its wide tropism but also represents a new therapeutic target to limit COVID-19 spreading. Although Axl’s involvement in tumor progression has been known for many years, different drugs targeting this receptor have already been developed and commercialized, fostering studies about their repurposing in COVID-19 management. As preclinical studies using Axl inhibitors such as bemcentinib and gilteritinib showed promising results [84,85,86,87,95], bemcentinib is under clinical trials to evaluate its effectiveness in treating SARS-CoV-2 infection [88,89], while it has been reported that gilteritinib administration in an acute myeloid leukemia patient ameliorated COVID-19 symptoms [90].

In addition to these studies investigating Axl’s role as an alternative receptor for SARS-CoV-2 cell entry, a recent study focused on Axl involvement in COVID-19 pathogenesis, especially in the epithelial-to-mesenchymal transition (EMT) process [91]. The SARS-CoV-2 infection has been shown to upregulate different oncogenic pathways, including EMT [91,100]. Such an alteration in the adhesive properties of epithelial cells, especially in the lung district could thus be involved in altering air/blood barrier permeability, finally resulting in impaired respiratory function, typical of severe COVID-19. Considering Axl’s role in regulating EMT, Stewart and coworkers hypothesized that reverting EMT using Axl inhibitors such as bemcentinib, which displays a proven in vitro antiviral efficacy against SARS-CoV-2, could represent an attractive option to limit COVID-19 severity [91].