Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Konrad Hoeft; Gideon J L Schaefer; Hyojin Kim; David Schumacher; Tore Bleckwehl; Qingqing Long; Barbara Mara Klinkhammer; Fabian Peisker; Lars Koch; James Nagai; Maurice Halder; Susanne Ziegler; Elisa Liehn; Christoph Kuppe; Jennifer Kranz; Sylvia Menzel; Ivan Costa; Adam Wahida; Peter Boor; Rebekka K Schneider; Sikander Hayat; Rafael Kramann

doi:10.1016/j.celrep.2023.112131

Platelet-instructed SPP1⁺ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner

Cell Rep. 2023 Feb 28;42(2):112131. doi: 10.1016/j.celrep.2023.112131. Epub 2023 Feb 18.

Authors

Konrad Hoeft¹, Gideon J L Schaefer¹, Hyojin Kim², David Schumacher³, Tore Bleckwehl², Qingqing Long², Barbara Mara Klinkhammer⁴, Fabian Peisker², Lars Koch¹, James Nagai⁵, Maurice Halder², Susanne Ziegler², Elisa Liehn⁶, Christoph Kuppe¹, Jennifer Kranz⁷, Sylvia Menzel², Ivan Costa⁵, Adam Wahida⁸, Peter Boor⁹, Rebekka K Schneider¹⁰, Sikander Hayat², Rafael Kramann¹¹

Affiliations

¹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
² Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
³ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Department of Anesthesiology, RWTH Aachen University, Aachen, Germany.
⁴ Department of Pathology, RWTH Aachen University, Aachen, Germany.
⁵ Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany.
⁶ Institute for Molecular Medicine, University of South Denmark, Odense, Denmark.
⁷ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Department of Urology, RWTH Aachen University, Aachen, Germany; Department of Urology and Kidney Transplantation, Martin-Luther-University, Halle (Saale), Germany.
⁸ Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany; Division of Gynecological Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Department of Pathology, RWTH Aachen University, Aachen, Germany.
¹⁰ Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Cell Biology, Institute for Biomedical Technologies, RWTH Aachen University, Aachen, Germany.
¹¹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: rkramann@gmx.net.

Abstract

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo, drive profibrotic Spp1 macrophage differentiation. Single nuclear RNA sequencing with ligand-receptor interaction analysis reveals that macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk. Finally, we confirm that Spp1 macrophages expand in both human chronic kidney disease and heart failure.

Keywords: CP: Immunology; CXCL4; PF4; SPP1; SPP1 macrophages; chronic kidney disease; fibrosis; heart failure; innate immunity; myocardial infarction; platelets.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fibrosis
Humans
Ligands
Macrophages* / metabolism
Myofibroblasts* / metabolism
Osteopontin
Platelet Factor 4 / genetics
Platelet Factor 4 / metabolism

Substances

Ligands
Osteopontin
Platelet Factor 4
SPP1 protein, human
PF4 protein, human