Rico-Llanos, GustavoPorras-Perales, OscarEscalante, SandraVazquez-Calero, Daniel BValiente, LuciaCastillo, Maria IPerez-Tejeiro, Jose MiguelBaglietto-Vargas, DavidBecerra, JoseReguera, Jose MariaDuran, IvanCsukasi, Fabiana2023-05-032023-05-032022-11-18Rico-Llanos G, Porras-Perales Ó, Escalante S, Vázquez-Calero DB, Valiente L, Castillo MI, et al. Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP. Front Immunol. 2022 Nov 18;13:1054962http://hdl.handle.net/10668/20598Inflammation 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.enAttribution 4.0 Internationalhttp://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 BiPLungresearch article36466830open accessInflamaciónNeumoníaPulmónMacrófagos AlveolaresSíndrome de Dificultad Respiratoria10.3389/fimmu.2022.10549621664-3224PMC9716134https://www.frontiersin.org/articles/10.3389/fimmu.2022.1054962/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716134/pdf