Blockade of IL-6 Signaling Alleviates Atherosclerosis in -deficient Clonal Hematopoiesis

Overview

Journal Nat Cardiovasc Res

Publisher Springer Nature

Specialty Cardiology & Vascular Diseases

Date 2023 Aug 4

PMID 37539077

Authors

Wenli Liu

Mustafa Yalcinkaya

Ines Fernandez Maestre

Malgorzata Olszewska

Patrick B Ampomah

J Brett Heimlich

Ranran Wang

Pablo Sanchez Vela

Tong Xiao

Alexander G Bick

Ross Levine

Eirini P Papapetrou

Peter Libby

Ira Tabas

Nan Wang

Alan R Tall

Affiliations

Soon will be listed here.

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 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of in -deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human -deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in CH mice. Our study demonstrates the causality of IL-6 signaling in 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.

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