Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry
Li, W.; Tu, L. N.; Hsieh, L.; Smith, J. R.; Yeh, Y.-T.; Sinyagin, A.; Ghassemian, M.; Timms, A.; Charette, K.; Mauchley, D.; McMullan, M.; Bohuta, L.; Greene, C.; Regier, M.; del Alamo, J. C.; Savan, R.; Nigam, V.
Show abstract
Patients undergoing cardiac surgery face significant inflammatory induced by exposure to cardiopulmonary bypass (CPB), contributing to heightened morbidity and mortality. The molecular and cellular mechanisms that underpin this inflammatory process remain unknown. To address this knowledge gap, we performed snRNA/ATAC-Sequencing on leukocytes from neonatal CPB patients. Classical monocytes become more prevalent and have dysregulation of inflammatory genes after CPB, indicating their role in CPB-associated inflammation. A genome-wide CRISPR screen and in vitro experiments in non-adherent monocytic cells identified two novel genes, SPTAN1 and RAF1, as effectors of hemodynamic stress. SPTAN1 and RAF1 activate store-operated calcium entry that results inflammation and cell death. snATAC-Seq revealed dynamically changing patterns of chromatin accessibility and AP-1 transcription factor binding after CPB exposure. These findings provide novel insights into the pathogenesis of CPB-associated inflammation, with broad implications for understanding the early stages of sterile inflammation and how non-adherent cells sense shear stress.
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