Abstract
Background: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. Methods: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. Results: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. Conclusions: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.
Highlights
ConclusionsPlasma Growth arrest-specific factor 6 (GAS6) and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19
The body possesses restorative mechanisms, early triggered by pathogen and damage-associated molecular patterns (PAMPs and DAMPs), to counterbalance this pro-inflammatory response. One such protection system consists of vitamin K-dependent plasma proteins, which require carboxylation to become biologically active, and that serve as ligands for tyrosine kinase receptors of the Tyro3, AXL, and MERTK (TAM)
We prospectively measured the concentration of Growth arrest-specific factor 6 (GAS6), soluble AXL (sAXL) and Soluble MERTK (sMERTK) in 132 consecutive patients admitted to the emergency ward of “Hospital Clínico Universitario de Valladolid” (Valladolid, single university hospital in Valladolid (Spain))
Summary
GAS6 serum levels in patients admitted to the emergency ward were higher in SARSCoV-2-positive patients, increasing progressively with the severity of the disease. Deceased COVID-19 patients exhibited higher plasma concentration of sAXL and sMERTK at the time of emergency entry. AXL inhibition reduced cytokine production upon LPS challenge in THP-1 human macrophages, which exhibited AXL overexpression upon activation. These results support a relevant role of the GAS6/AXL system in the immune response against COVID-19, suggesting them as early markers of disease prognosis and GAS6/AXL targeting as plausible clinical therapy for COVID-19 patients
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