B-1a Cells and Acute Inflammation

About This Grant

PROJECT SUMMARY: Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are life-threatening conditions lacking effective treatments. ALI is frequently caused by sepsis or ischemia- reperfusion (I/R) injury, both severe inflammatory disorders. In this project we plan to investigate the critical role of B-1a cells, an immunoregulatory B cell subset, in mitigating ALI. We have discovered that B-1a cells are significantly reduced during sepsis or gut I/R injury, leading to exacerbated ALI. Conversely, we have also shown that adoptive transfer of B-1a cells rescues mice from ALI, highlighting their protective role. Our preliminary findings reveal that B-1a cell depletion occurs in ALI via neutrophil-mediated trogocytosis, a piecemeal phagocytic process. We discovered a novel interaction between Siglec-G and CD47, a “don’t-eat- me” signal receptor, on B-1a cells. This interaction disrupts the protective "don't-eat-me" signaling pathway, normally mediated by SIRPα on neutrophils, leading to B-1a cell trogocytosis. Furthermore, B-1a cells play a pivotal role in the metabolic function and survival of pulmonary endothelial cells (ECs). Therefore, preventing B-1a cell depletion is crucial for mitigating ALI. We have identified Compound 11 (C11), a novel 11-amino acid oligopeptide derived from CD47, which binds to Siglec-G. C11 inhibits the interaction of Siglec-G with CD47, thereby restoring the "don't-eat-me" function of B-1a cells. We, therefore, hypothesize that B-1a cell depletion in ALI occurs via neutrophil-mediated trogocytosis, and that C11 can ameliorate ALI by preventing this depletion. As such, we will elucidate the molecular mechanisms by which Siglec-G disrupts the CD47 "don't- eat-me" signal, leading to B-1a cell trogocytosis by neutrophils. We will also investigate how B-1a cells promote lung EC metabolic function and survival. Finally, the therapeutic potential of C11 will be evaluated in preclinical models to assess its ability to preserve B-1a cells, restore EC metabolic function, and reduce ALI severity. Therefore, this project enhances our understanding of ALI pathophysiology, and highlights C11 as a potential breakthrough in ALI therapy, offering new hope for patients battling this critical illness.