Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP

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 sub...

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Published in:Frontiers in immunology 2022-11, Vol.13, p.1054962-1054962
Main Authors: Rico-Llanos, Gustavo, Porras-Perales, Óscar, Escalante, Sandra, Vázquez-Calero, Daniel B., Valiente, Lucía, Castillo, María I., Pérez-Tejeiro, José Miguel, Baglietto-Vargas, David, Becerra, José, Reguera, José María, Duran, Ivan, Csukasi, Fabiana
Format: Article
Language:English
Subjects:
acute respiratory distress syndrome
binding-immunoglobulinprotein (BiP/GRP78/HSPA5)
cell surface GRP78 (csGRP78)
cellular stress
COVID-19
cytokine storm
Immunology
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Summary: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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2022.1054962