1. Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP
- Author
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Gustavo Rico-Llanos, Óscar Porras-Perales, Sandra Escalante, Daniel B. Vázquez-Calero, Lucía Valiente, María I. Castillo, José Miguel Pérez-Tejeiro, David Baglietto-Vargas, José Becerra, José María Reguera, Ivan Duran, and Fabiana Csukasi
- Subjects
COVID-19 ,acute respiratory distress syndrome ,binding-immunoglobulinprotein (BiP/GRP78/HSPA5) ,cytokine storm ,cell surface GRP78 (csGRP78) ,cellular stress ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Inflammation 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.
- Published
- 2022
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