Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).
Weiskirchen, R., Weiskirchen, S. & Tacke, F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Mol. Asp. Med 65, 2–15 (2019).
Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Investig. 122, 787–795 (2012).
Rakina, M., Larionova, I. & Kzhyshkowska, J. Macrophage diversity in human cancers: new insight provided by single-cell resolution and spatial context. Heliyon 10, e28332 (2024).
Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).
Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604 (2010).
Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).
Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).
Jiang, Y. et al. Macrophages in organ fibrosis: from pathogenesis to therapeutic targets. Cell Death Discov. 10, 487 (2024).
Wuyts, W. A. et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur. Respir. J. 41, 1207–1218 (2013).
Wijsenbeek, M. & Cottin, V. Spectrum of fibrotic lung diseases. N. Engl. J. Med. 383, 958–968 (2020).
Richeldi, L., Collard, H. R. & Jones, M. G. Idiopathic pulmonary fibrosis. Lancet 389, 1941–1952 (2017).
Lederer, D. J. & Martinez, F. J. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 379, 797–798 (2018).
Ley, B., Collard, H. R. & King, T. E. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 183, 431–440 (2011).
Martinez, F. J. et al. Idiopathic pulmonary fibrosis. Nat. Rev. Dis. Primers 3, 17074 (2017).
Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).
Kamiya, M. et al. Immune mechanisms in fibrotic interstitial lung disease. Cell 187, 3506–3530 (2024).
Larson-Casey, J. L. et al. Myeloid heterogeneity mediates acute exacerbations of pulmonary fibrosis. J. Immunol. 211, 1714–1724 (2023).
Zandi, S. et al. ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep. 10, 1173–1186 (2015).
Sasaki, F. et al. Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. JCI Insight 3, e96902 (2018).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Chen, S., Yang, J., Wei, Y. & Wei, X. Epigenetic regulation of macrophages: from homeostasis maintenance to host defense. Cell Mol. Immunol. 17, 36–49 (2020).
Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).
Klose, R. J. & Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nat. Rev. Mol. Cell Biol. 8, 307–318 (2007).
Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016).
Huang, C. et al. Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Res. 20, 154–165 (2010).
Horton, J. R. et al. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat. Struct. Mol. Biol. 17, 38–43 (2010).
Ming, H. et al. The nuclear bodies formed by histone demethylase KDM7A. Protein Cell 12, 297–304 (2021).
Swaminathan, J. et al. Cross-talk between histone methyltransferases and demethylases regulate REST transcription during neurogenesis. Front. Oncol. 12, 855167 (2022).
Higashijima, Y. et al. Lysine demethylase 7a regulates murine anterior-posterior development by modulating the transcription of Hox gene cluster. Commun. Biol. 3, 725 (2020).
Adams, T. S. et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci. Adv. 6, eaba1983 (2020).
Habermann, A. C. et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci. Adv. 6, eaba1972 (2020).
Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).
Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Baer, J. M. et al. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC. Nat. Immunol. 24, 1443–1457 (2023).
Chávez-Galán, L., Olleros, M. L., Vesin, D. & Garcia, I. Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front. Immunol. 6, 263 (2015).
Gibbons, M. A. et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am. J. Respir. Crit. Care Med 184, 569–581 (2011).
Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163–172 (2019).
Strunz, M. et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 11, 3559 (2020).
Atabai, K. et al. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Investig. 119, 3713–3722 (2009).
Yombo, D. J. K., Odayar, V., Gupta, N., Jegga, A. G. & Madala, S. K. The protective effects of IL-31RA deficiency during bleomycin-induced pulmonary fibrosis. Front. Immunol. 12, 645717 (2021).
Noskovičová, N., Petřek, M., Eickelberg, O. & Heinzelmann, K. Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am. J. Respir. Cell Mol. Biol. 52, 263–284 (2015).
Moore, B. B. et al. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am. J. Respir. Cell Mol. Biol. 35, 175–181 (2006).
Yang, J. et al. Diverse injury pathways induce alveolar epithelial cell CCL2/12, which promotes lung fibrosis. Am. J. Respir. Cell Mol. Biol. 62, 622–632 (2020).
Baluk, P. et al. Lymphatic proliferation ameliorates pulmonary fibrosis after lung injury. Am. J. Pathol. 190, 2355–2375 (2020).
Murray, L. A. et al. Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis. JCI Insight 2, e92192 (2017).
Geeraerts, X., Bolli, E., Fendt, S. M. & Van Ginderachter, J. A. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front. Immunol. 8, 289 (2017).
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A. & Sancho, D. Metabolism of tissue macrophages in homeostasis and pathology. Cell Mol. Immunol. 19, 384–408 (2022).
Kieler, M., Hofmann, M. & Schabbauer, G. More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization. FEBS J. 288, 3694–3714 (2021).
de-Brito, M. et al. Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages. Biochim. Biophys. Acta Mol. Cell Res. 1867, 118604 (2020).
Zhao, Q. et al. 2-Deoxy-d-glucose treatment decreases anti-inflammatory M2 macrophage polarization in mice with tumor and allergic airway inflammation. Front. Immunol. 8, 637 (2017).
Chen, S. et al. The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. Genes Dev. 26, 1364–1375 (2012).
Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
Zhang, Z. J. et al. TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J. Exp. Med. 215, 3019–3037 (2018).
Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018).
Singh, M. et al. Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J. Immunol. 193, 4722–4731 (2014).
Lech, M. & Anders, H. J. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim. Biophys. Acta 1832, 989–997 (2013).
Kitchen, G. B. et al. The histone methyltransferase Ezh2 restrains macrophage inflammatory responses. FASEB J. 35, e21843 (2021).
Xu, R. et al. Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4. Cell Death Dis. 12, 22 (2021).
Sim, D. Y. et al. Suppression of STAT3 phosphorylation and RelA/p65 acetylation mediated by MicroRNA134 plays a pivotal role in the apoptotic effect of lambertianic acid. Int. J. Mol. Sci. 20, 2993 (2019).
Bitzer, M. et al. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev. 14, 187–197 (2000).
Chakarov, S. et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363, eaau0964 (2019).
Etoh, K. et al. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers. Cell Rep. 43, 114496 (2024).
Soto-Palma, C., Niedernhofer, L. J., Faulk, C. D. & Dong, X. Epigenetics, DNA damage, and aging. J Clin. Investig. 132, e158446 (2022).
Tanaka, H. et al. The NSD2/WHSC1/MMSET methyltransferase prevents cellular senescence-associated epigenomic remodeling. Aging Cell 19, e13173 (2020).
Wang, K. et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal. Transduct. Target Ther. 7, 374 (2022).
Bied, M., Ho, W. W., Ginhoux, F. & Blériot, C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol. Immunol. 20, 983–992 (2023).
Revelo, X. S. et al. Cardiac resident macrophages prevent fibrosis and stimulate angiogenesis. Circ. Res. 129, 1086–1101 (2021).
Alzaid, F. et al. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight 1, e88689 (2016).
Suzuki, T. et al. Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity. J. Med. Chem. 56, 7222–7231 (2013).
Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat. Chem. Biol. 1, 143–145 (2005).
Pan, M. R., Hsu, M. C., Chen, L. T. & Hung, W. C. Orchestration of H3K27 methylation: mechanisms and therapeutic implication. Cell Mol. Life Sci. 75, 209–223 (2018).
Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).
Schiller, H. B. et al. Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair. Mol. Syst. Biol. 11, 819 (2015).
Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).
Takase, R. et al. Lysine-specific demethylase-2 is distinctively involved in brown and beige adipogenic differentiation. FASEB J. 33, 5300–5311 (2019).
Hino, S., Sato, T. & Nakao, M. Chromatin immunoprecipitation sequencing (ChIP-seq) for detecting histone modifications and modifiers. Methods Mol. Biol. 2577, 55–64 (2023).
Sud, M. et al. Metabolomics Workbench: an international repository for metabolomics data and metadata, metabolite standards, protocols, tutorials and training, and analysis tools. Nucleic Acids Res. 44, D463–D470 (2016).
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).