2. Academic Validation
  3. A shear stress-responsive pathway in monocytes drives cardiopulmonary bypass-induced inflammation via spectrin/RAF1/store-operated calcium entry

A shear stress-responsive pathway in monocytes drives cardiopulmonary bypass-induced inflammation via spectrin/RAF1/store-operated calcium entry

  • Cell Rep. 2026 Feb 24;45(2):116903. doi: 10.1016/j.celrep.2025.116903.
Weiming Li 1,  Lan N Tu 1,  Lance Hsieh 1,  Julian R Smith 2,  Yi-Ting Yeh 3,  Anthony Sinyagin 1,  Eric G B Evans 1,  Majid Ghassemian 4,  Andrew Timms 5,  Kevin Charette 6,  David Mauchley 6,  Michael McMullan 6,  Lyubomyr Bohuta 6,  Christina Greene 6,  Mary C Regier 7,  Juan Carlos Del Alamo 3,  Ram Savan 2,  Vishal Nigam 8
Affiliations

Affiliations

  • 1 Department of Pediatrics (Cardiology), University of Washington, Seattle, WA, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
  • 2 Department of Immunology, University of Washington, Seattle, WA, USA.
  • 3 Department of Mechanical Engineering, University of Washington, Seattle, WA, USA.
  • 4 Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA, USA.
  • 5 Department of Pediatrics (Cardiology), University of Washington, Seattle, WA, USA.
  • 6 Division of Pediatric Cardiac Surgery, Seattle Children's Hospital, Seattle, WA, USA.
  • 7 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • 8 Department of Pediatrics (Cardiology), University of Washington, Seattle, WA, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA. Electronic address: [email protected].
PMID: 41579376 DOI: 10.1016/j.celrep.2025.116903
Abstract

Cardiopulmonary bypass (CPB) during cardiac surgery triggers inflammation that increases morbidity and mortality, though its molecular mechanisms remain unknown. To address this gap, we conducted single-nucleus RNA/ATAC Sequencing (snRNA-seq/snATAC-seq) to profile transcriptional- and chromatin-level changes in circulating leukocytes from neonatal patients who underwent CPB. Classical monocytes increase after CPB, show dysregulated inflammatory genes, and exhibit altered chromatin accessibility, underscoring their role in CPB-associated inflammation. Expression of the proinflammatory cytokine interleukin-8 (IL-8/CXCL8) is significantly upregulated after CPB exposure, accompanied by increased accessibility of its promoter to AP-1 transcription factors. A genome-wide CRISPR screen in THP-1 cells identified SPTAN1 and RAF1 as novel effectors of hemodynamic stress. We further found that SPTAN1 and RAF1 activate store-operated calcium entry under CPB conditions, leading to elevated IL8 expression. We identify a shear stress-responsive SPTAN1/RAF1/store-operated calcium entry (SOCE) pathway and show that targeting it may alleviate CPB-induced inflammation, providing new insights into sterile inflammation and shear sensing in non-adherent cells.

Keywords

CP: Immunology; CP: Molecular biology; cardiac defects; cardiopulmonary bypass; inflammation; shear stress.

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