Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis

  • Nat Cardiovasc Res. 2023 Jun;2(6):572-586. doi: 10.1038/s44161-023-00281-3.
Wenli Liu  1  2 ,  Mustafa Yalcinkaya  1 ,  Inés Fernández Maestre  3  4 ,  Malgorzata Olszewska  5  6  7 ,  Patrick B Ampomah  8 ,  J Brett Heimlich  9 ,  Ranran Wang  1 ,  Pablo Sánchez Vela  3 ,  Tong Xiao  1 ,  Alexander G Bick  10 ,  Ross Levine  3 ,  Eirini P Papapetrou  5  6  7 ,  Peter Libby  11 ,  Ira Tabas  1 ,  Nan Wang  1  2 ,  Alan R Tall  1  2
Affiliations
  • 1. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA.
  • 2. These authors contributed equally: Wenli Liu, Nan Wang, Alan R. Tall.
  • 3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4. Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8. Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • 9. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 10. Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 11. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 37539077 DOI: 10.1038/s44161-023-00281-3
Abstract

Clonal hematopoiesis (CH) increases the risk of atherosclerotic Cardiovascular Disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by TET2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in TET2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human TET2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in TET2 CH mice. Our study demonstrates the causality of IL-6 signaling in TET2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven Cardiovascular Disease.

Products