Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug–Gene Networks: From Biology to Precision Therapeutics

Author:

Decano Julius L.1ORCID,Maiorino Enrico2ORCID,Matamalas Joan T.1ORCID,Chelvanambi Sarvesh1ORCID,Tiemeijer Bart M.1ORCID,Yanagihara Yoshihiro1ORCID,Mukai Shin1ORCID,Jha Prabhash Kumar3,Pestana Diego V.S.1ORCID,D’Souza Edwin1ORCID,Whelan Mary1ORCID,Ge Rile1ORCID,Asano Takaharu1,Sharma Amitabh12,Libby Peter3ORCID,Singh Sasha A.1ORCID,Aikawa Elena13ORCID,Aikawa Masanori123ORCID

Affiliation:

1. Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., J.T.M., S.C., B.M.T., Y.Y., S.M., D.V.S.P., E.D., M.W., R.G., T.A., A.S., S.A.S., E.A., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

2. Channing Division of Network Medicine (E.M., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

3. Department of Medicine, and Center for Excellence in Vascular Biology (P.K.J., P.L., E.A., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Abstract

BACKGROUND: Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions. METHODS: Primary human macrophages activated by IFNγ (M(IFNγ)) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis. RESULTS: Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M(IFNγ) i ) and phagocytic (M(IFNγ) p ). M(IFNγ) i had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ) p . M(IFNγ) p were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ) i . Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ) i subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ) i subpopulation while expanding the M(IFNγ) p subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification. CONCLUSIONS: We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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