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
  • 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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