Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome
Albert Morales,
Silvia Rojo Rello,
Helena Cristóbal,
Aida Fiz-López,
Elisa Arribas,
Montserrat Marí,
Anna Tutusaus,
Paloma de la Cal-Sabater,
Gerry A.F. Nicolaes,
José T. Ortiz-Pérez,
David Bernardo,
Pablo García de Frutos
Affiliations
Albert Morales
Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain
Silvia Rojo Rello
Servicio de Microbiología, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain
Helena Cristóbal
Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain
Aida Fiz-López
Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain
Elisa Arribas
Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain
Montserrat Marí
Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain
Anna Tutusaus
Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain
Paloma de la Cal-Sabater
Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain
Gerry A.F. Nicolaes
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands
José T. Ortiz-Pérez
Clinic Cardiovascular Institute, Hospital Clinic Barcelona, 08036 Barcelona, Spain
David Bernardo
Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain
Pablo García de Frutos
Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain
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.
