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

Front Immunol. 2022 Nov 18;13:1054962. doi: 10.3389/fimmu.2022.1054962. eCollection 2022.


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.

Keywords: 4-PBA; COVID-19; TNFa; acute respiratory distress syndrome; binding-immunoglobulinprotein (BiP/GRP78/HSPA5); cell surface GRP78 (csGRP78); cellular stress; cytokine storm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Endoplasmic Reticulum Chaperone BiP
  • Humans
  • Inflammation
  • Lung
  • Respiratory Distress Syndrome*
  • SARS-CoV-2


  • Endoplasmic Reticulum Chaperone BiP