Targeting immune–fibroblast cell communication in heart failure

• Published in: Nature (London) 2024-11, Vol.635 (8038), p.423-433
• Main Authors: Amrute, Junedh M., Luo, Xin, Penna, Vinay, Yang, Steven, Yamawaki, Tracy, Hayat, Sikander, Bredemeyer, Andrea, Jung, In-Hyuk, Kadyrov, Farid F., Heo, Gyu Seong, Venkatesan, Rajiu, Shi, Sally Yu, Parvathaneni, Alekhya, Koenig, Andrew L., Kuppe, Christoph, Baker, Candice, Luehmann, Hannah, Jones, Cameran, Kopecky, Benjamin, Zeng, Xue, Bleckwehl, Tore, Ma, Pan, Lee, Paul, Terada, Yuriko, Fu, Angela, Furtado, Milena, Kreisel, Daniel, Kovacs, Atilla, Stitziel, Nathan O., Jackson, Simon, Li, Chi-Ming, Liu, Yongjian, Rosenthal, Nadia A., Kramann, Rafael, Ason, Brandon, Lavine, Kory J.
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/31; 13/51; 14; 38; 45; 59/78; 631/250/256; 631/337/2019; 631/443/592/75/230; 64; 64/60; Animal models; Animals; CC chemokine receptors; Cell Adhesion Molecules - metabolism; Cell Communication - immunology; Cell interactions; Cell Lineage; Chemokine receptors; Chemokines; Chromatin; Chromatin - metabolism; Congestive heart failure; Coronary artery disease; Cytokines; Disease; Disease Models, Animal; Endopeptidases - metabolism; Epigenetics; Epitope Mapping; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene expression; Gene mapping; Genetic analysis; Heart diseases; Heart failure; Heart Failure - immunology; Heart Failure - pathology; Human performance; Humanities and Social Sciences; Humans; IL-1β; Inflammation; Injury analysis; Interleukin 1 receptors; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Ischemia; Ligands; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Membrane Proteins - metabolism; Mice; Molecular modelling; Monoclonal antibodies; Monocyte chemoattractant protein 1; Monocytes; Monocytes - immunology; Monocytes - metabolism; multidisciplinary; Multiomics; Myocardial Infarction - immunology; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; Myofibroblasts - metabolism; Myofibroblasts - pathology; Peptide mapping; Phenotypes; Proteins; Quality control; Receptors, CCR2 - metabolism; Science; Science (multidisciplinary); Serine Endopeptidases - metabolism; Signal Transduction; Single-Cell Analysis; Spatial analysis; Transcriptomics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08008-5

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction 1 , 2 . However, the molecular mechanisms driving immune–fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis 3 , 4 . Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP + fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand–receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2 + monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function. A fibroblast lineage marked by FAP gives rise to POSTN-expressing fibroblasts resembling matrifibrocytes and IL-1β regulates FAP/POSTN fibroblast specification by directly signalling to cardiac fibroblasts, highlighting a role for immunomodulators in targeting cardiac fibrosis.