Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunology of human fibrosis

Nature Immunology volume 24, pages 1423–1433 (2023)Cite this article

Subjects

Abstract

Fibrosis, defined by the excess deposition of structural and matricellular proteins in the extracellular space, underlies tissue dysfunction in multiple chronic diseases. Approved antifibrotics have proven modest in efficacy, and the immune compartment remains, for the most part, an untapped therapeutic opportunity. Recent single-cell analyses have interrogated human fibrotic tissues, including immune cells. These studies have revealed a conserved profile of scar-associated macrophages, which localize to the fibrotic niche and interact with mesenchymal cells that produce pathological extracellular matrix. Here we review recent advances in the understanding of the fibrotic microenvironment in human diseases, with a focus on immune cell profiles and functional immune–stromal interactions. We also discuss the key role of the immune system in mediating fibrosis regression and highlight avenues for future study to elucidate potential approaches to targeting inflammatory cells in fibrotic disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Tissular diversity of fibrosis.
Fig. 2: Conserved monocyte-derived SAMac phenotype within the fibrotic niche across different tissues10.
Fig. 3: Profibrotic priming of fibroblasts by IL-1β.
Fig. 4: Fibrosis regression.

Similar content being viewed by others

References

  1. Wynn, T. A. Fibrotic disease and the TH1/TH2 paradigm. Nat. Rev. Immunol. 4, 583–594 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Taylor, R. S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 158, 1611–1625 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Moon, A. M., Singal, A. G. & Tapper, E. B. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin. Gastroenterol. Hepatol. 18, 2650–2666 (2020).

    Article  PubMed  Google Scholar 

  4. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019). scRNA-seq study of healthy versus fibrotic human liver, defining the transcriptional profile of SAMacs and studying ligand–receptor interactions in the fibrotic niche.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buonomo, E. L. et al. Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages. J. Hepatol. 76, 1127–1137 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Hendrikx, T. et al. Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH. J. Hepatol. 77, 1373–1385 (2022).

    Article  CAS  PubMed  Google Scholar 

  7. Remmerie, A. et al. Osteopontin expression identifies a subset of recruited macrophages distinct from kupffer cells in the fatty liver. Immunity 53, 641–657 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xiong, X. et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol. Cell 75, 644–660 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Daemen, S. et al. Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 34, 108626 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fabre, T. et al. Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci. Immunol. 8, eadd8945 (2023). Integrated analysis of lung and liver scRNA-seq data from human and mouse, defining the conserved features of SAMacs across organs. Highlights the role of GM-CSF, IL-17A and TGFβ in SAMac differentiation.

    Article  CAS  PubMed  Google Scholar 

  11. Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Govaere, O. et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Sci. Transl. Med. 12, eaba4448 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Poch, T. et al. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis. J. Hepatol. 75, 414–423 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rau, M. et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of TH17 cells in the liver and an increased TH17/resting regulatory T cell ratio in peripheral blood and in the liver. J. Immunol. 196, 97–105 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Dudek, M. et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592, 444–449 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Pallett, L. J. et al. Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS. Nature 614, 334–342 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Wang, S. et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 15, eadd3949 (2023).

    Article  CAS  PubMed  Google Scholar 

  19. Wallace, S. J., Tacke, F., Schwabe, R. F. & Henderson, N. C. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Rep. 4, 100524 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ramachandran, P., Matchett, K. P., Dobie, R., Wilson-Kanamori, J. R. & Henderson, N. C. Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nat. Rev. Gastroenterol. Hepatol. 17, 457–472 (2020).

    Article  PubMed  Google Scholar 

  21. Lederer, D. J. & Martinez, F. J. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 378, 1811–1823 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Wolters, P. J., Collard, H. R. & Jones, K. D. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev. Pathol. 9, 157–179 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. 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). scRNA-seq study from human lung fibrosis. A web-based browser of this and other articles is available at http://ipfcellatlas.com

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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). scRNA-seq study from human lung fibrosis. A web-based browser of this and other articles is available at http://ipfcellatlas.com

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reyfman, P. A. et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am. J. Respir. Crit. Care Med 199, 1517–1536 (2019). scRNA-seq study from human lung fibrosis. A web-based browser of this and other articles is available at http://ipfcellatlas.com

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morse, C. et al. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur. Respir. J. 54, 1802441 (2019). scRNA-seq study from human lung fibrosis. A web-based browser of this and other articles is available at http://ipfcellatlas.com

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163–172 (2019). Experimental models of lung fibrosis demonstrating the role of monocyte-derived macrophages in the early fibrotic stage after injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wendisch, D. et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 184, 6243–6261 (2021). Analysis of fibrotic changes in COVID-19 lung samples with comparison to IPF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu, X. et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir. Med 9, 747–754 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Faverio, P. et al. One-year pulmonary impairment after severe COVID-19: a prospective, multicenter follow-up study. Respir. Res 23, 65 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leslie, J. et al. FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis. JCI Insight 5, e125937 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Deng, L., Huang, T. & Zhang, L. T cells in idiopathic pulmonary fibrosis: crucial but controversial. Cell Death Discov. 9, 62 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ichikawa, T. et al. CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells. Nat. Immunol. 20, 1469–1480 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W. & Wynn, T. A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fallon, P. G., Richardson, E. J., McKenzie, G. J. & McKenzie, A. N. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585–2591 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Cheever, A. W. et al. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing TH2 cytokines while decreasing egg-induced hepatic fibrosis. J. Immunol. 153, 753–759 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Raghu, G. et al. SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772). Eur. Respir. J. 52, 1801130 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Maher, T. M. et al. Phase 2 trial to assess lebrikizumab in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 57, 1902442 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Allanore, Y. et al. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 79, 1600–1607 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Jha, V. et al. Chronic kidney disease: global dimension and perspectives. Lancet 382, 260–272 (2013).

    Article  PubMed  Google Scholar 

  41. Li, L., Fu, H. & Liu, Y. The fibrogenic niche in kidney fibrosis: components and mechanisms. Nat. Rev. Nephrol. 18, 545–557 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Kuppe, C. et al. Decoding myofibroblast origins in human kidney fibrosis. Nature 589, 281–286 (2021). scRNA-seq study of healthy versus fibrotic human kidney, generating a cell atlas and highlighting myeloid–mesenchymal interactions.

  43. Hoeft, K. et al. Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell Rep. 42, 112131 (2023). Analysis of human and mouse kidney and cardiac macrophages identifying conserved SAMac populations and demonstrating role of CXCL4 in the generation of SAMacs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Conway, B. R. et al. Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease. J. Am. Soc. Nephrol. 31, 2833–2854 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Doke, T. et al. Single-cell analysis identifies the interaction of altered renal tubules with basophils orchestrating kidney fibrosis. Nat. Immunol. 23, 947–959 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. Basile, D. P., Ullah, M. M., Collet, J. A. & Mehrotra, P. T helper 17 cells in the pathophysiology of acute and chronic kidney disease. Kidney Res. Clin. Pract. 40, 12–28 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Frangogiannis, N. G. Cardiac fibrosis. Cardiovasc Res. 117, 1450–1488 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Miranda, A. M. A. et al. Single-cell transcriptomics for the assessment of cardiac disease. Nat. Rev. Cardiol. 20, 289–308 (2022).

    Article  PubMed  Google Scholar 

  49. Koenig, A. L. et al. Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat. Cardiovasc. Res. 1, 263–280 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Reichart, D. et al. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science 377, eabo1984 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lavine, K. et al. Targeting immune–fibroblast crosstalk in myocardial infarction and cardiac fibrosis. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-2402606/v1 (2023). Single-cell and spatial analysis of human and mouse cardiac fibrosis, defining disease-associated macrophages and changes in T cells. Identification of IL-1β+ macrophages in the fibrotic niche and demonstration that IL-1β modulation inhibits fibrosis.

  52. Kuppe, C. et al. Spatial multi-omic map of human myocardial infarction. Nature 608, 766–777 (2022). Multiomic analysis of human post-MI hearts, highlighting myeloid–mesenchymal spatial interactions in cardiac repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rao, M. et al. Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level. Basic Res. Cardiol. 116, 55 (2021).

    Article  PubMed  Google Scholar 

  54. Dick, S. A. et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 20, 29–39 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Revelo, X. S. et al. Cardiac resident macrophages prevent fibrosis and stimulate angiogenesis. Circ. Res. 129, 1086–1101 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chaffin, M. et al. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy. Nature 608, 174–180 (2022).

    Article  CAS  PubMed  Google Scholar 

  58. Alexanian, M. et al. Chromatin remodeling drives immune–fibroblast crosstalk in heart failure pathogenesis. Preprint at bioRxiv https://doi.org/10.1101/2023.01.06.522937 (2023).

  59. Deniset, J. F. et al. Gata6+ pericardial cavity macrophages relocate to the injured heart and prevent cardiac fibrosis. Immunity 51, 131–140 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Litvinukova, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ong, S. et al. Natural killer cells limit cardiac inflammation and fibrosis by halting eosinophil infiltration. Am. J. Pathol. 185, 847–861 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Satoh, T. et al. Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature 541, 96–101 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Misharin, A. V. et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J. Exp. Med. 214, 2387–2404 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Tang, P. M., Nikolic-Paterson, D. J. & Lan, H. Y. Macrophages: versatile players in renal inflammation and fibrosis. Nat. Rev. Nephrol. 15, 144–158 (2019).

    Article  PubMed  Google Scholar 

  66. Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Krenkel, O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 67, 1270–1283 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67, 1754–1767 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Buechler, M. B., Fu, W. & Turley, S. J. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity 54, 903–915 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Ding, L. et al. Bone marrow CD11c+ cell-derived amphiregulin promotes pulmonary fibrosis. J. Immunol. 197, 303–312 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Perugorria, M. J. et al. Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut 68, 533–546 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Labiano, I. et al. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. J. Hepatol. 77, 991–1004 (2022).

    Article  CAS  PubMed  Google Scholar 

  73. Li, Z. et al. Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy. Cell Rep. Med 3, 100699 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Raslan, A. A. et al. Single cell transcriptomics of fibrotic lungs unveils aging-associated alterations in endothelial and epithelial cell regeneration. Preprint at bioRxiv https://doi.org/10.1101/2023.01.17.523179 (2023).

  75. Eyres, M. et al. Spatially resolved deconvolution of the fibrotic niche in lung fibrosis. Cell Rep. 40, 111230 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chung, B. K., Ogaard, J., Reims, H. M., Karlsen, T. H. & Melum, E. Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis. Hepatol. Commun. 6, 2538–2550 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).

    Article  CAS  PubMed  Google Scholar 

  78. Tsukui, T. et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 11, 1920 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Boyd, D. F. et al. Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature 587, 466–471 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356–365 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tsukui, T. & Sheppard, D. Tracing the origin of pathologic pulmonary fibroblasts. Preprint at bioRxiv https://doi.org/10.1101/2022.11.18.517147 (2022).

  82. Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nguyen, H. N. et al. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 46, 220–232 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ng, B. et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci. Transl. Med. 11, eaaw1237 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110–115 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhou, X. et al. Circuit design features of a stable two-cell system. Cell 172, 744–757 (2018). This study explains the concept of macrophage–fibroblast circuits and how they regulate cell proliferation and steady-state proportions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Adler, M. et al. Principles of cell circuits for tissue repair and fibrosis. iScience 23, 100841 (2020). This study explains the concept of macrophage–fibroblast circuits in fibrosis and the idea of ‘hot’ v ‘cold’ fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Setten, E. et al. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context. Nat. Commun. 13, 6499 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481–518 (2022).

    Article  CAS  PubMed  Google Scholar 

  90. Wei, K., Nguyen, H. N. & Brenner, M. B. Fibroblast pathology in inflammatory diseases. J. Clin. Invest. 131, e149538 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lodyga, M. et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β. Sci. Signal 12, eaao3469 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Umetsu, D. T., Katzen, D., Jabara, H. H. & Geha, R. S. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J. Immunol. 136, 440–445 (1986).

    Article  CAS  PubMed  Google Scholar 

  93. Kundig, T. M. et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268, 1343–1347 (1995).

    Article  CAS  PubMed  Google Scholar 

  94. Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ngwenyama, N. et al. Antigen presentation by cardiac fibroblasts promotes cardiac dysfunction. Nat. Cardiovasc. Res. 1, 761–774 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Sutherland, T. E., Dyer, D. P. & Allen, J. E. The extracellular matrix and the immune system: a mutually dependent relationship. Science 379, eabp8964 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Zhuo, L. et al. SHAP potentiates the CD44-mediated leukocyte adhesion to the hyaluronan substratum. J. Biol. Chem. 281, 20303–20314 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. McQuitty, C. E., Williams, R., Chokshi, S. & Urbani, L. Immunomodulatory role of the extracellular matrix within the liver disease microenvironment. Front. Immunol. 11, 574276 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69–74 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tharp, K. M. et al. Myeloid mechano-metabolic programming restricts anti-tumor immunity. Preprint at bioRxiv https://doi.org/10.1101/2022.07.14.499764 (2022).

  103. Pakshir, P. et al. Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix. Nat. Commun. 10, 1850 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Marcellin, P. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381, 468–475 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Lassailly, G. et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 159, 1290–1301 (2020).

    Article  PubMed  Google Scholar 

  106. Izawa, H. et al. Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 112, 2940–2945 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Diez, J. et al. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105, 2512–2517 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Prabhu, S. et al. Regression of diffuse ventricular fibrosis following restoration of sinus rhythm with catheter ablation in patients with atrial fibrillation and systolic dysfunction: a substudy of the CAMERA MRI Trial. JACC Clin. Electrophysiol. 4, 999–1007 (2018).

    Article  PubMed  Google Scholar 

  109. Fioretto, P., Steffes, M. W., Sutherland, D. E., Goetz, F. C. & Mauer, M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N. Engl. J. Med. 339, 69–75 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Fioretto, P., Sutherland, D. E., Najafian, B. & Mauer, M. Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int. 69, 907–912 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012). This study demonstrates the role of a subpopulation of matrix-degrading monocyte-derived macrophages in liver fibrosis regression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    Article  CAS  PubMed  Google Scholar 

  113. Rantakari, P. et al. Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury. Proc. Natl Acad. Sci. USA 113, 9298–9303 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Takimoto, Y. et al. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 26, 106220 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pellicoro, A. et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology 55, 1965–1975 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Fallowfield, J. A. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288–5295 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Ren, J. et al. Twist1 in infiltrating macrophages attenuates kidney fibrosis via matrix metallopeptidase 13-mediated matrix degradation. J. Am. Soc. Nephrol. 30, 1674–1685 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. McKleroy, W., Lee, T. H. & Atabai, K. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 304, L709–L721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cui, H. et al. Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution. JCI Insight 5, e134539 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Atabai, K. et al. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J. Clin. Invest. 119, 3713–3722 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Madsen, D. H. et al. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J. Cell Biol. 202, 951–966 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Campana, L. et al. The STAT3–IL-10–IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J. Immunol. 200, 1169–1187 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Hu, M. et al. Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis. Nat. Nanotechnol. 16, 466–477 (2021).

    Article  CAS  PubMed  Google Scholar 

  124. Saijou, E. et al. Neutrophils alleviate fibrosis in the CCl4-induced mouse chronic liver injury model. Hepatol. Commun. 2, 703–717 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Calvente, C. J. et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J. Clin. Invest. 129, 4091–4109 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Hegde, P. et al. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nat. Commun. 9, 2146 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Mabire, M. et al. MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming. Nat. Commun. 14, 1830 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Baeck, C. et al. Pharmacological inhibition of the chemokine C–C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C+ macrophage infiltration in mice. Hepatology 59, 1060–1072 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Kisseleva, T. & Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 18, 151–166 (2021).

    Article  PubMed  Google Scholar 

  130. Radaeva, S. et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130, 435–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Koda, Y. et al. CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat. Commun. 12, 4474 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sagiv, A. et al. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene 32, 1971–1977 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Troeger, J. S. et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073–1083 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schwantes-An, T. H. et al. Genome-wide association study and meta-analysis on alcohol-associated liver cirrhosis identifies genetic risk factors. Hepatology 73, 1920–1931 (2021).

    Article  CAS  PubMed  Google Scholar 

  137. Anstee, Q. M. et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. J. Hepatol. 73, 505–515 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Allen, R. J. et al. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med 201, 564–574 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nauffal, V. et al. Genetics of myocardial interstitial fibrosis in the human heart and association with disease. Nat. Genet. 55, 777–786 (2023).

    Article  CAS  PubMed  Google Scholar 

  140. Murtha, L. A. et al. The role of pathological aging in cardiac and pulmonary fibrosis. Aging Dis. 10, 419–428 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Kim, I. H., Kisseleva, T. & Brenner, D. A. Aging and liver disease. Curr. Opin. Gastroenterol. 31, 184–191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lee, S. et al. Molecular programs of fibrotic change in aging human lung. Nat. Commun. 12, 6309 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gullotta, G. S. et al. Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. Nat. Immunol. 24, 925–940 (2023).

    Article  CAS  PubMed  Google Scholar 

  146. Mogilenko, D. A., Shchukina, I. & Artyomov, M. N. Immune ageing at single-cell resolution. Nat. Rev. Immunol. 22, 484–498 (2022).

    Article  CAS  PubMed  Google Scholar 

  147. De Maeyer, R. P. H. & Chambers, E. S. The impact of ageing on monocytes and macrophages. Immunol. Lett. 230, 1–10 (2021).

    Article  PubMed  Google Scholar 

  148. Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Abozaid, Y. J. et al. Plasma proteomic signature of fatty liver disease: the Rotterdam Study. Hepatology https://doi.org/10.1097/HEP.0000000000000300 (2023).

  150. Sanyal, A. J. et al. Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 78, 693–703 (2023).

    Article  CAS  PubMed  Google Scholar 

  151. Bowman, W. S. et al. Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis. Lancet Respir. Med 10, 593–602 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. McGlinchey, A. J. et al. Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease. JHEP Rep. 4, 100477 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Seeliger, B. et al. Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication. Front Pharm. 13, 837680 (2022).

    Article  CAS  Google Scholar 

  154. Sacchi, M., Bansal, R. & Rouwkema, J. Bioengineered 3D models to recapitulate tissue fibrosis. Trends Biotechnol. 38, 623–636 (2020).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.B. is supported by a US DOD CDMRP Investigator-Initiated Research Award (W81XWH2110417). P.R. is supported by a Medical Research Council Senior Clinical Fellowship (MR/W015919/1). Images were made with copyright (M.B.) using Biorender.

Author information

Authors and Affiliations

  1. Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Mallar Bhattacharya

  2. University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh BioQuarter, Edinburgh, UK

    Prakash Ramachandran

Authors
  1. Mallar Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prakash Ramachandran
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.B. and P.R. conceived and co-wrote the manuscript, with equal contribution.

Corresponding authors

Correspondence to Mallar Bhattacharya or Prakash Ramachandran.

Ethics declarations

Competing interests

M.B has performed consultancy work for Merck and Ono Pharma. P.R. has received research support from Genentech, Intercept Pharmaceuticals, and NeoGenomics. P.R. has performed consultancy work for Merck.

Peer review

Peer review information

Nature Immunology thanks Thomas Wynn and Matthew Buechler for their contribution to the peer review of this work. Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhattacharya, M., Ramachandran, P. Immunology of human fibrosis. Nat Immunol 24, 1423–1433 (2023). https://doi.org/10.1038/s41590-023-01551-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-023-01551-9

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing