Rico-Llanos, GustavoPorras-Perales, ÓscarEscalante, SandraVázquez-Calero, Daniel BValiente, LucíaCastillo, María IPérez-Tejeiro, José MiguelBaglietto-Vargas, DavidBecerra, JoséReguera, José MaríaDuran, IvanCsukasi, Fabiana2024-02-272024-02-272022-11-18http://hdl.handle.net/10668/20598http://hdl.handle.net/20.500.12105/18855Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we observed increased levels of cell surface BiP (cs-BiP) in leukocytes during inflammation. This corresponds with a higher number of neutrophiles, which show naturally high levels of cs-BiP, whereas alveolar macrophages show a higher than usual exposure of BiP in their cell surface. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.engVoRhttp://creativecommons.org/licenses/by/4.0/4-PBACOVID-19TNFaacute respiratory distress syndromebinding-immunoglobulinprotein (BiP/GRP78/HSPA5)cell surface GRP78 (csGRP78)cellular stresscytokine stormHumansCOVID-19SARS-CoV-2Respiratory Distress SyndromeInflammationEndoplasmic Reticulum Chaperone BiPLungAttribution 4.0 International3646683013105496210.3389/fimmu.2022.10549621664-3224Frontiers in immunologyopen access