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

Wenli Liu1,2, Mustafa Yalcinkaya1, Inés Fernández Maestre3,4

  • 1Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA.

Nature Cardiovascular Research
|August 4, 2023
PubMed

Insights

Clonal hematopoiesis (CH) drives cardiovascular disease risk. Blocking interleukin-6 (IL-6) signaling reverses this by reducing inflammation and macrophage activity, offering a potential therapy for CH-related heart conditions.

Area of Science:

  • Cardiovascular Science
  • Immunology
  • Hematology

Background:

  • Clonal hematopoiesis (CH) is linked to increased atherosclerotic cardiovascular disease (ASCVD) risk, potentially via inflammation.
  • Interleukin-6 (IL-6) signaling is implicated in CH-driven ASCVD, especially in TET2 mutations.

Purpose of the Study:

  • To investigate the causal role of IL-6 signaling in Tet2 CH-driven atherosclerosis.
  • To identify the underlying mechanisms linking IL-6, Tet2 deficiency, and cardiovascular disease.

Main Methods:

  • Utilized IL-6 receptor antibody treatment in mouse models of Tet2 CH.
  • Investigated IL-6-induced changes in macrophage gene expression (CSF1R) and survival.
  • Examined the effect of a CSF1R inhibitor (PLX3397) on atherosclerosis.

Main Results:

  • IL-6 receptor antibody treatment reversed atherosclerosis in Tet2 CH mice, reducing monocytosis and macrophage burden.
  • IL-6 enhances macrophage colony-stimulating factor 1 receptor (CSF1R) expression in Tet2-deficient macrophages via STAT3.
  • CSF1R inhibition also reversed accelerated atherosclerosis in Tet2 CH mice.

Conclusions:

  • IL-6 signaling causally drives atherosclerosis in Tet2 CH.
  • IL-6-induced CSF1R expression is a critical mechanism in this process.
  • Blocking IL-6 signaling presents a potential therapeutic strategy for CH-associated cardiovascular disease.

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