Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo
Laura Bouchareychas,
Phat Duong,
Sergio Covarrubias,
Eric Alsop,
Tuan Anh Phu,
Allen Chung,
Michael Gomes,
David Wong,
Bessie Meechoovet,
Allyson Capili,
Ryo Yamamoto,
Hiromitsu Nakauchi,
Michael T. McManus,
Susan Carpenter,
Kendall Van Keuren-Jensen,
Robert L. Raffai
Affiliations
Laura Bouchareychas
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Phat Duong
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Sergio Covarrubias
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
Eric Alsop
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Tuan Anh Phu
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Allen Chung
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Michael Gomes
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
David Wong
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Bessie Meechoovet
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Allyson Capili
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
Ryo Yamamoto
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Hiromitsu Nakauchi
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Michael T. McManus
Department of Microbiology and Immunology, UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
Susan Carpenter
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
Kendall Van Keuren-Jensen
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Robert L. Raffai
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Corresponding author
Summary: Developing strategies that promote the resolution of vascular inflammation and atherosclerosis remains a major therapeutic challenge. Here, we show that exosomes produced by naive bone marrow-derived macrophages (BMDM-exo) contain anti-inflammatory microRNA-99a/146b/378a that are further increased in exosomes produced by BMDM polarized with IL-4 (BMDM-IL-4-exo). These exosomal microRNAs suppress inflammation by targeting NF-κB and TNF-α signaling and foster M2 polarization in recipient macrophages. Repeated infusions of BMDM-IL-4-exo into Apoe−/− mice fed a Western diet reduce excessive hematopoiesis in the bone marrow and thereby the number of myeloid cells in the circulation and macrophages in aortic root lesions. This also leads to a reduction in necrotic lesion areas that collectively stabilize atheroma. Thus, BMDM-IL-4-exo may represent a useful therapeutic approach for atherosclerosis and other inflammatory disorders by targeting NF-κB and TNF-α via microRNA cargo delivery.
