Abstract
Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.
Key points
-
Fibroblasts assume multifaceted roles in regulating immunity, guiding tissue architecture and remodelling and defining the functional organization of tissues.
-
During disease, fibroblasts can acquire inflammatory, fibrogenic, tissue degradative or hyperplastic phenotypes that promote pathology and predominate in treatment resistance.
-
Although long implicated in fibrotic disease, fibroblasts have emerged as important drivers and regulators of chronic inflammatory and malignant diseases.
-
Single-cell profiling of diseased tissues has uncovered transcriptionally and functionally distinct fibroblast subpopulations, some of which are tissue specific or disease specific and others of which are shared across multiple tissues and diseases.
-
Morphogen gradients, synergistic and autocrine cytokine signalling, adhesion molecules, mechanotransducers and epigenetic regulators are some of the key factors that promote the differentiation and activation of pathogenic fibroblast states.
-
Insights into fibroblast pathogenicity are spurring the development of therapeutics to deplete, deactivate, neutralize or reprogram fibroblasts in fibrosis, cancer and chronic inflammatory diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Virchow, R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre: Pionierarbeit der Zellpathologie und Gewebelehre im 19. Jahrhundert. (Good Press, 1858).
Dulbecco, R., Allen, R., Okada, S. & Bowman, M. Functional changes of intermediate filaments in fibroblastic cells revealed by a monoclonal antibody. Proc. Natl Acad. Sci. USA 80, 1915–1918 (1983).
Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).
Muhl, L. et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 11, 3953 (2020).
Mor-Vaknin, N., Punturieri, A., Sitwala, K. & Markovitz, D. M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 5, 59–63 (2003).
Li, R. et al. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. eLife 7, e36865 (2018).
Chandrakanthan, V. et al. Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta. Nat. Cell Biol. 24, 1211–1225 (2022).
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148 (2022).
Fan, D., Takawale, A., Lee, J. & Kassiri, Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5, 15 (2012).
Friedrich, M. et al. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat. Med. 27, 1970–1981 (2021).
Rivellese, F. et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat. Med. 28, 1256–1268 (2022).
Zhang, F. et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 623, 616–624 (2023).
Kelly, T., Huang, Y., Simms, A. E. & Mazur, A. Fibroblast activation protein-ɑ: a key modulator of the microenvironment in multiple pathologies. Int. Rev. Cell Mol. Biol. 297, 83–116 (2012).
Kiener, H. P. et al. Cadherin-11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 60, 1305–1310 (2009).
Roberts, E. W. et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).
Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).
Malhotra, D. et al. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13, 499–510 (2012).
Gravallese, E. M. & Firestein, G. S. Rheumatoid arthritis — common origins, divergent mechanisms. N. Engl. J. Med. 388, 529–542 (2023).
Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. JAMA 320, 1360–1372 (2018).
Smolen, J. S. & Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015).
Smith, M. D. The normal synovium. Open Rheumatol. J. 5, 100–106 (2011).
Hochberg, M. C. et al. Rheumatology (Elsevier, 2023).
Fletcher, A. L., Acton, S. E. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat. Rev. Immunol. 15, 350–361 (2015).
Perez-Shibayama, C., Gil-Cruz, C. & Ludewig, B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunol. Rev. 289, 31–41 (2019).
Li, L., Wu, J., Abdi, R., Jewell, C. M. & Bromberg, J. S. Lymph node fibroblastic reticular cells steer immune responses. Trends Immunol. 42, 723–734 (2021).
Onder, L. & Ludewig, B. A fresh view on lymph node organogenesis. Trends Immunol. 39, 775–787 (2018).
van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Katakai, T. et al. Organizer-like reticular stromal cell layer common to adult secondary lymphoid organs. J. Immunol. 181, 6189–6200 (2008).
Roozendaal, R. et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 30, 264–276 (2009).
Cremasco, V. et al. B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat. Immunol. 15, 973–981 (2014).
Tew, J. G. et al. Follicular dendritic cells and presentation of antigen and costimulatory signals to B cells. Immunol. Rev. 156, 39–52 (1997).
Qin, D. et al. Fcγ receptor IIB on follicular dendritic cells regulates the B cell recall response. J. Immunol. 164, 6268–6275 (2000).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Acton, SophieE. et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 37, 276–289 (2012).
Lee, J.-W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8, 181–190 (2007).
Magnusson, F. C. et al. Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity. Gastroenterology 134, 1028–1037 (2008).
Fletcher, A. L. et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 207, 689–697 (2010).
Baptista, A. P. et al. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. eLife 3, e04433 (2014).
Lukacs-Kornek, V. et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat. Immunol. 12, 1096–1104 (2011).
Siegert, S. et al. Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS ONE 6, e27618 (2011).
Pinchuk, I. V. et al. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 135, 1228–1237 (2008).
Owens, B. M. et al. CD90+ stromal cells are non-professional innate immune effectors of the human colonic mucosa. Front. Immunol. 4, 307 (2013).
Das, A. et al. Follicular dendritic cell activation by TLR ligands promotes autoreactive B cell responses. Immunity 46, 106–119 (2017).
Zeng, Q. et al. Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses. Cell Metab. 35, 837–854 e838 (2023).
Karouzakis, E. et al. Molecular characterization of human lymph node stromal cells during the earliest phases of rheumatoid arthritis. Front. Immunol. 10, 1863 (2019).
Mellors, R. C., Heimer, R., Corcos, J. & Korngold, L. Cellular origin of rheumatoid factor. J. Exp. Med. 110, 875–886 (1959).
Nosanchuk, J. S. & Schintzier, B. Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis. A clinicopathologic study. Cancer 24, 343–354 (1969).
Shapira, Y., Weinberger, A. & Wysenbeek, A. J. Lymphadenopathy in systemic lupus erythematosus. Prevalence and relation to disease manifestations. Clin. Rheumatol. 15, 335–338 (1996).
Cook, M. The size and histological appearances of mesenteric lymph nodes in Crohn’s disease. Gut 13, 970 (1972).
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).
West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).
Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).
Ivashkiv, L. B. Cytokine expression and cell activation in inflammatory arthritis. Adv. Immunol. 63, 337–376 (1996).
Sponheim, J. et al. Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am. J. Pathol. 177, 2804–2815 (2010).
Boots, A. M., Wimmers-Bertens, A. J. & Rijnders, A. W. Antigen-presenting capacity of rheumatoid synovial fibroblasts. Immunology 82, 268–274 (1994).
Tran, C. N. et al. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes. Arthritis Rheum. 56, 1497–1506 (2007).
Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628–636 (2008).
Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).
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).
Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of 100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).
Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).
DeLeon-Pennell, K. Y., Barker, T. H. & Lindsey, M. L. Fibroblasts: the arbiters of extracellular matrix remodeling. Matrix Biol. 91–92, 1–7 (2020).
Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).
Valencia, X. et al. Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J. Exp. Med. 200, 1673–1679 (2004).
Eckes, B. et al. Mechanical tension and integrin ɑ2β1 regulate fibroblast functions. J. Investig. Dermatol. Symp. Proc. 11, 66–72 (2006).
Li, B. & Wang, J. H. Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J. Tissue Viability 20, 108–120 (2011).
Levick, J. R. & McDonald, J. N. Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann. Rheum. Dis. 54, 417–423 (1995).
Gretz, J. E., Anderson, A. O. & Shaw, S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156, 11–24 (1997).
Astarita, J. L. et al. The CLEC-2–podoplanin axis controls fibroblastic reticular cell contractility and lymph node microarchitecture. Nat. Immunol. 16, 75–84 (2015).
Desmouliere, A., Chaponnier, C. & Gabbiani, G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 13, 7–12 (2005).
Distler, J. H. W. et al. Shared and distinct mechanisms of fibrosis. Nat. Rev. Rheumatol. 15, 705–730 (2019).
Zeisberg, M. & Kalluri, R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 304, C216–C225 (2013).
Tolboom, T. C. et al. Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann. Rheum. Dis. 61, 975–980 (2002).
Tunyogi-Csapo, M. et al. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum. 58, 2397–2408 (2008).
Gregorieff, A. et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).
McCarthy, N. et al. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26, 391–402.e395 (2020).
Brugger, M. D., Valenta, T., Fazilaty, H., Hausmann, G. & Basler, K. Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis. PLoS Biol. 18, e3001032 (2020).
Liu, Y. et al. Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state. Dev. Cell 57, 1758–1775.e1757 (2022).
Wei, K. et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 582, 259–264 (2020).
Rinn, J. L. et al. A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev. 22, 303–307 (2008).
Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).
Knosp, W. M., Scott, V., Bachinger, H. P. & Stadler, H. S. HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis. Development 131, 4581–4592 (2004).
Dieu-Nosjean, M. C., Goc, J., Giraldo, N. A., Sautes-Fridman, C. & Fridman, W. H. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).
Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 477 (2016).
Nayar, S. et al. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc. Natl Acad. Sci. USA 116, 13490–13497 (2019).
Manzo, A. et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur. J. Immunol. 35, 1347–1359 (2005).
Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).
Kobayashi, I. & Ziff, M. Electron microscopic studies of the cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum. 18, 475–483 (1975).
Kuhn, C. & McDonald, J. A. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am. J. Pathol. 138, 1257–1265 (1991).
Rodriguez, A. B. et al. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36, 109422 (2021).
Zhang, Y. et al. CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis. Cancer Cell 42, 1370–1385.e9 (2024).
Yang, C. Y. et al. Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes. Proc. Natl Acad. Sci. USA 111, E109–E118 (2014).
Hecker, L., Jagirdar, R., Jin, T. & Thannickal, V. J. Reversible differentiation of myofibroblasts by MyoD. Exp. Cell Res. 317, 1914–1921 (2011).
Garrison, G. et al. Reversal of myofibroblast differentiation by prostaglandin E2. Am. J. Respir. Cell Mol. Biol. 48, 550–558 (2013).
Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).
Filer, A. & Buckley, C. D. et al. in Rheumatology (ed. Hochberg, M. C.) 1–7 (Elsevier, 2023).
Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).
Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).
Donlin, L. T. et al. Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue. Arthritis Res. Ther. 20, 139 (2018).
Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).
Armaka, M. et al. Single-cell multimodal analysis identifies common regulatory programs in synovial fibroblasts of rheumatoid arthritis patients and modeled TNF-driven arthritis. Genome Med. 14, 78 (2022).
Mueller, A. A. et al. Wnt signaling drives stromal inflammation in inflammatory arthritis. Preprint at bioRxiv https://doi.org/10.1101/2025.01.06.631510 (2025).
MacLauchlan, S. et al. Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res. Ther. 19, 166 (2017).
Lewis, M. J. et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 28, 2455–2470.e2455 (2019).
Faust, H. J. et al. Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis. Nat. Commun. 15, 9859 (2024).
Rauber, S. et al. CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis. Nat. Immunol. 25, 682–692 (2024).
Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481–518.e14 (2022).
Tian, L., Chen, F. & Macosko, E. Z. The expanding vistas of spatial transcriptomics. Nat. Biotechnol. 41, 773–782 (2023).
Lake, B. B. et al. An atlas of healthy and injured cell states and niches in the human kidney. Nature 619, 585–594 (2023).
Wu, H. et al. High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing. Nat. Commun. 15, 1396 (2024).
Madissoon, E. et al. A spatially resolved atlas of the human lung characterizes a gland-associated immune niche. Nat. Genet. 55, 66–77 (2023).
Vannan, A. et al. Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis. Nat. Genet. 57, 647–658 (2025).
Fawkner-Corbett, D. et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810–826.e823 (2021).
Qi, J. et al. Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nat. Commun. 13, 1742 (2022).
Reis Nisa, P. et al. Spatial programming of fibroblasts promotes resolution of tissue inflammation through immune cell exclusion. Preprint at bioRxiv https://doi.org/10.1101/2024.09.20.614064 (2024).
Periyakoil, P. K. et al. Deep topic modeling of spatial transcriptomics in the rheumatoid arthritis synovium identifies distinct classes of ectopic lymphoid structures. Preprint at bioRxiv https://doi.org/10.1101/2025.01.08.631928 (2025).
Bhamidipati, K. et al. Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis. Preprint at bioRxiv https://doi.org/10.1101/2025.03.14.642821 (2025).
Vickovic, S. et al. Three-dimensional spatial transcriptomics uncovers cell type localizations in the human rheumatoid arthritis synovium. Commun. Biol. 5, 129 (2022).
Smith, M. H. et al. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis. Nat. Immunol. 24, 1200–1210 (2023).
Zheng, L. et al. ITGA5+ synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis. Ann. Rheum. Dis. 84, 232–252 (2025).
Zhao, S. et al. Effect of JAK inhibition on the induction of proinflammatory HLA–DR+CD90+ rheumatoid arthritis synovial fibroblasts by interferon-γ. Arthritis Rheumatol. 74, 441–452 (2022).
Seibl, R. et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am. J. Pathol. 162, 1221–1227 (2003).
Kim, K. W. et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol. Lett. 110, 54–64 (2007).
Goh, F. G. & Midwood, K. S. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology 51, 7–23 (2012).
Chabaud, M., Fossiez, F., Taupin, J. L. & Miossec, P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J. Immunol. 161, 409–414 (1998).
Zrioual, S. et al. Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J. Immunol. 182, 3112–3120 (2009).
Slowikowski, K. et al. CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts. Proc. Natl Acad. Sci. USA 117, 5532–5541 (2020).
Hartupee, J., Liu, C., Novotny, M., Li, X. & Hamilton, T. IL-17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 4135–4141 (2007).
MacNaul, K. L., Chartrain, N., Lark, M., Tocci, M. J. & Hutchinson, N. I. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-1 and tumor necrosis factor-ɑ on stromelysin expression. J. Biol. Chem. 265, 17238–17245 (1990).
Ainola, M. M. et al. Pannus invasion and cartilage degradation in rheumatoid arthritis: involvement of MMP-3 and interleukin-1β. Clin. Exp. Rheumatol. 23, 644–650 (2005).
Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110–115 (2017).
Kuo, D. et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci. Transl. Med. 11, eaau8587 (2019).
Yan, M. et al. ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nat. Immunol. 23, 1330–1341 (2022).
Nguyen, H. N. et al. Leukemia inhibitory factor (LIF) receptor amplifies pathogenic activation of fibroblasts in lung fibrosis. Proc. Natl Acad. Sci. USA 121, e2401899121 (2024).
Xiao, Y. & MacRae, I. J. Toward a comprehensive view of microRNA biology. Mol. Cell 75, 666–668 (2019).
Trenkmann, M. et al. Tumor necrosis factor α-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling. Arthritis Rheum. 65, 916–927 (2013).
Stanczyk, J. et al. Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001–1009 (2008).
Nakasa, T. et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58, 1284–1292 (2008).
Long, L. et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. J. Immunol. Res. 2013, 296139 (2013).
Saferding, V. et al. MicroRNA-146a governs fibroblast activation and joint pathology in arthritis. J. Autoimmun. 82, 74–84 (2017).
Churov, A. V., Oleinik, E. K. & Knip, M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun. Rev. 14, 1029–1037 (2015).
Iborra, M., Bernuzzi, F., Invernizzi, P. & Danese, S. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun. Rev. 11, 305–314 (2012).
O’Reilly, S. MicroRNAs in fibrosis: opportunities and challenges. Arthritis Res. Ther. 18, 11 (2016).
Aprelikova, O. & Green, J. E. MicroRNA regulation in cancer-associated fibroblasts. Cancer Immunol. Immunother. 61, 231–237 (2012).
Eckes, B. et al. Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol. 19, 325–332 (2000).
Janmey, P. A., Fletcher, D. A. & Reinhart-King, C. A. Stiffness sensing by cells. Physiol. Rev. 100, 695–724 (2020).
Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).
Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).
Vandooren, B. et al. Tumor necrosis factor ɑ drives cadherin 11 expression in rheumatoid inflammation. Arthritis Rheum. 58, 3051–3062 (2008).
Schneider, D. J. et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).
Wu, M. et al. Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol. 66, 1010–1021 (2014).
Schroer, A. K. et al. Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction. JCI Insight 4, e131545 (2019).
Stanford, S. M. et al. Receptor protein tyrosine phosphatase α–mediated enhancement of rheumatoid synovial fibroblast signaling and promotion of arthritis in mice. Arthritis Rheumatol. 68, 359–369 (2016).
Sendo, S. et al. Clustering of phosphatase RPTPɑ promotes Src signaling and the arthritogenic action of synovial fibroblasts. Sci. Signal. 16, eabn8668 (2023).
Lo, C.-M., Wang, H.-B., Dembo, M. & Wang, Y.-l. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79, 144–152 (2000).
Gu, Z. et al. Soft matrix is a natural stimulator for cellular invasiveness. Mol. Biol. Cell 25, 457–469 (2014).
Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L344–L357 (2015).
Southern, B. D. et al. Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. J. Biol. Chem. 291, 6083–6095 (2016).
Cambré, I. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun. 9, 4613 (2018).
Müller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).
Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233, 233–255 (2010).
Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 5, 40 (2013).
Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).
Orange, D. E. et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N. Engl. J. Med. 383, 218–228 (2020).
Nile, C. J., Read, R. C., Akil, M., Duff, G. W. & Wilson, A. G. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 58, 2686–2693 (2008).
Karouzakis, E. et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes. Immun. 12, 643–652 (2011).
Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. & Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72, 110–117 (2013).
de la Rica, L. et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J. Autoimmun. 41, 6–16 (2013).
Araki, Y. et al. Histone methylation and STAT-3 differentially regulate interleukin-6-induced matrix metalloproteinase gene activation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 68, 1111–1123 (2016).
Lee, A. et al. Tumor necrosis factor ɑ induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 65, 928–938 (2013).
Loh, C. et al. TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis. Ann. Rheum. Dis. 78, 1205–1214 (2019).
Sohn, C. et al. Prolonged tumor necrosis factor alpha primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 67, 86–95 (2015).
Friščić, J. et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 54, 1002–1021.e10 (2021).
Weinand, K. et al. The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis. Nat. Commun. 15, 4650 (2024).
Ai, R. et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat. Commun. 9, 1921 (2018).
Ai, R. et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980 (2015).
Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).
Ai, R. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat. Commun. 7, 11849 (2016).
Hammaker, D. et al. Joint location–specific JAK-STAT signaling in rheumatoid arthritis fibroblast-like synoviocytes. ACR Open Rheumatol. 1, 640–648 (2019).
Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit. Nat. Rev. Drug. Discov. 17, 197–223 (2018).
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).
van de Donk, N. & Zweegman, S. T-cell-engaging bispecific antibodies in cancer. Lancet 402, 142–158 (2023).
Fenis, A., Demaria, O., Gauthier, L., Vivier, E. & Narni-Mancinelli, E. New immune cell engagers for cancer immunotherapy. Nat. Rev. Immunol. 24, 471–486 (2024).
Busek, P., Mateu, R., Zubal, M., Kotackova, L. & Sedo, A. Targeting fibroblast activation protein in cancer — prospects and caveats. Front. Biosci. 23, 1933–1968 (2018).
Xin, L. et al. Fibroblast activation protein-ɑ as a target in the bench-to-bedside diagnosis and treatment of tumors: a narrative review. Front. Oncol. 11, 648187 (2021).
Scott, A. M. et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).
McConathy, J. et al. 671P LuMIERE: a phase I/II study evaluating safety, dosimetry, and preliminary activity of [177Lu]Lu-FAP-2286 in patients with advanced solid tumors. Ann. Oncol. 35, S526 (2024).
Shahvali, S., Rahiman, N., Jaafari, M. R. & Arabi, L. Targeting fibroblast activation protein (FAP): advances in CAR-T cell, antibody, and vaccine in cancer immunotherapy. Drug. Deliv. Transl. Res. 13, 2041–2056 (2023).
Chai, X. P. et al. Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-ɑ. Acta Pharmacol. Sin. 39, 415–424 (2018).
Cui, X. Y. et al. Covalent targeted radioligands potentiate radionuclide therapy. Nature 630, 206–213 (2024).
Loureiro, L. R. et al. Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment. J. Exp. Clin. Cancer Res. 42, 341 (2023).
de Sostoa, J. et al. Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J. Immunother. Cancer 7, 19 (2019).
Hiltbrunner, S. et al. Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial. Ann. Oncol. 32, 120–121 (2021).
Bocci, M. et al. In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment. J. Control. Rel. 367, 779–790 (2024).
Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019).
Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).
Dorst, D. N. et al. Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy. Rheumatology 61, 2999–3009 (2022).
Mori, Y. et al. FAPI PET: fibroblast activation protein inhibitor use in oncologic and nononcologic disease. Radiology 306, e220749 (2023).
Chavula, T., To, S. & Agarwal, S. K. Cadherin-11 and its role in tissue fibrosis. Cell Tissues Organs 212, 293–303 (2023).
Schett, G. et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat. Rev. Rheumatol. 20, 531–544 (2024).
Chung, J. B., Brudno, J. N., Borie, D. & Kochenderfer, J. N. Chimeric antigen receptor T cell therapy for autoimmune disease. Nat. Rev. Immunol. 24, 830–845 (2024).
Michaelson, J. S. & Baeuerle, P. A. CD19-directed T cell-engaging antibodies for the treatment of autoimmune disease. J. Exp. Med. 221, e20240499 (2024).
Shah, K. et al. Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy? Clin. Exp. Immunol. 217, 15–30 (2024).
Parayath, N. N., Stephan, S. B., Koehne, A. L., Nelson, P. S. & Stephan, M. T. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat. Commun. 11, 6080 (2020).
Zhao, Y. et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053–9061 (2010).
Bucci, L. et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat. Med. 30, 1593–1601 (2024).
Hagen, M. et al. BCMA-targeted T-cell-engager therapy for autoimmune disease. N. Engl. J. Med. 391, 867–869 (2024).
Alexander, T., Kronke, J., Cheng, Q., Keller, U. & Kronke, G. Teclistamab-induced remission in refractory systemic lupus erythematosus. N. Engl. J. Med. 391, 864–866 (2024).
Heipertz, E. L. et al. Current perspectives on “off-the-shelf” allogeneic NK and CAR-NK cell therapies. Front. Immunol. 12, 732135 (2021).
Younesi, F. S., Miller, A. E., Barker, T. H., Rossi, F. M. V. & Hinz, B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat. Rev. Mol. Cell Biol. 25, 617–638 (2024).
Bhattacharya, M. & Ramachandran, P. Immunology of human fibrosis. Nat. Immunol. 24, 1423–1433 (2023).
Zhao, M. et al. Targeting fibrosis, mechanisms and clinical trials. Signal. Transduct. Target. Ther. 7, 206 (2022).
Klein, K. et al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 75, 422–429 (2016).
Neidhart, M., Karouzakis, E., Jungel, A., Gay, R. E. & Gay, S. Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis. Arthritis Rheumatol. 66, 1723–1733 (2014).
Kehrberg, R. J., Bhyravbhatla, N., Batra, S. K. & Kumar, S. Epigenetic regulation of cancer-associated fibroblast heterogeneity. Biochim. Biophys. Acta Rev. Cancer 1878, 188901 (2023).
Ulukan, B., Sila Ozkaya, Y. & Zeybel, M. Advances in the epigenetics of fibroblast biology and fibrotic diseases. Curr. Opin. Pharmacol. 49, 102–109 (2019).
Liu, Y. et al. Epigenetics as a versatile regulator of fibrosis. J. Transl. Med. 21, 164 (2023).
Fearon, U., Hanlon, M. M., Wade, S. M. & Fletcher, J. M. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. Clin. Exp. Immunol. 197, 170–180 (2019).
Hu, Z. et al. Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review. Front. Immunol. 15, 1250884 (2024).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Zhang, F. et al. Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution. J. Hematol. Oncol. 17, 80 (2024).
Hamanaka, R. B. & Mutlu, G. M. Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism. FEBS J. 288, 6331–6352 (2021).
Wang, S., Liang, Y. & Dai, C. Metabolic regulation of fibroblast activation and proliferation during organ fibrosis. Kidney Dis. 8, 115–125 (2022).
Noom, A., Sawitzki, B., Knaus, P. & Duda, G. N. A two-way street — cellular metabolism and myofibroblast contraction. NPJ Regen. Med. 9, 15 (2024).
Takahashi, S. et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 19, 76 (2017).
Song, G. et al. Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis. Arthritis Res. Ther. 21, 87 (2019).
Ahmed, S. et al. Dual inhibition of glycolysis and glutaminolysis for synergistic therapy of rheumatoid arthritis. Arthritis Res. Ther. 25, 176 (2023).
Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).
Koedderitzsch, K., Zezina, E., Li, L., Herrmann, M. & Biesemann, N. TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A. Sci. Rep. 11, 19385 (2021).
Becker, L. M. et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31, 107701 (2020).
Broz, M. T. et al. Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas. Nat. Commun. 15, 2498 (2024).
Cho, S. J., Moon, J. S., Lee, C. M., Choi, A. M. & Stout-Delgado, H. W. Glucose transporter 1-dependent glycolysis is increased during aging-related lung fibrosis, and phloretin inhibits lung fibrosis. Am. J. Respir. Cell Mol. Biol. 56, 521–531 (2017).
Yin, X. et al. Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β. Sci. Signal. 12, eaax4067 (2019).
Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e21 (2021).
Huynh, N. C.-N. et al. Oncostatin M-driven macrophage-fibroblast circuits as a drug target in autoimmune arthritis. Inflamm. Regen. 44, 36 (2024).
Tsaltskan, V. & Firestein, G. S. Targeting fibroblast-like synoviocytes in rheumatoid arthritis. Curr. Opin. Pharmacol. 67, 102304 (2022).
Finch, R. et al. Op0224 results of a phase 2 study of Rg6125, an anti-cadherin-11 monoclonal antibody, in rheumatoid arthritis patients with an inadequate response to anti-TNFalpha therapy. Ann. Rheum. Dis. 78, 189–189 (2019).
Scheller, J., Grötzinger, J. & Rose‐John, S. Updating interleukin‐6 classic‐and trans‐signaling. Signal. Transduct. 6, 240–259 (2006).
Choy, E. H. et al. Translating IL-6 biology into effective treatments. Nat. Rev. Rheumatol. 16, 335–345 (2020).
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M. & Scheller, J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat. Rev. Immunol. 23, 666–681 (2023).
Ruderman, E. M. Rheumatoid arthritis: IL-6 inhibition in RA-deja vu all over again? Nat. Rev. Rheumatol. 11, 321–322 (2015).
Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut 68, 40–48 (2019).
Haringman, J. J. et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 54, 2387–2392 (2006).
Vergunst, C. E. et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 58, 1931–1939 (2008).
Szekanecz, Z. & Koch, A. E. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 5–13 (2016).
Cambier, S., Gouwy, M. & Proost, P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol. Immunol. 20, 217–251 (2023).
Kurowska-Stolarska, M. & Alivernini, S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat. Rev. Rheumatol. 18, 384–397 (2022).
Hitchon, C. A. & El-Gabalawy, H. S. The synovium in rheumatoid arthritis. Open Rheumatol. J. 5, 107–114 (2011).
Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Firestein, G. S. & McInnes, I. B. Immunopathogenesis of rheumatoid arthritis. Immunity 46, 183–196 (2017).
Snir, O. et al. Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63, 2873–2883 (2011).
Moon, J. S. et al. Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis. Nat. Commun. 14, 319 (2023).
Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).
Donado, C. A. et al. Granzyme K activates the entire complement cascade. Nature https://doi.org/10.1038/s41586-025-08713-9 (2025).
Kongpachith, S. et al. Affinity maturation of the anti-citrullinated protein antibody paratope drives epitope spreading and polyreactivity in rheumatoid arthritis. Arthritis Rheumatol. 71, 507–517 (2019).
Acknowledgements
The authors thank the members of the Brenner laboratory for helpful discussions. A.E.Z. received grant support from the US National Institutes of Health (NIH) (F30AI174699, T32GM007753 and T32GM144273). A.A.M. received grant support from the NIH (K08AR083513, T32AR007530 and P30AR070253) and the Rheumatology Research Foundation. M.B.B. received grant support from the NIH (R01AR0637039 and P01AI148102).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
M.B.B. is on the scientific advisory board of GSK and Moderna, is a consultant to 4F0 Ventures and is a founder of Mestag Therapeutics. However, this Review does not discuss any of the therapeutics of their pipelines.
Peer review
Peer review information
Nature Reviews Rheumatology thanks George Kalliolias, Samuel Kemble and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Antibody-dependent cellular cytotoxicity
-
An immune response whereby antibodies tag a target cell, allowing immune cells, such as natural killer cells, to bind via their Fc receptors and release toxins to destroy the target cells.
- Chimeric antigen receptor T cells
-
(CAR T cells). Genetically engineered T cells that are designed to recognize unique surface targets on diseased cells, which enables precise identification and elimination of target cells.
- Cytokine release syndrome
-
A systemic inflammatory response caused by excessive cytokine release, which can be an adverse effect of CAR T cell therapy.
- FAPα inhibitor–drug conjugates
-
(FAPI–drug conjugates). Small molecules or small peptides with an affinity for fibroblast activation protein α that are conjugated with drug payloads or with imaging agents such as radioisotopes.
- Lymphodepletion
-
A chemotherapy or radiation-based regimen that reduces the number of circulating lymphocytes prior to CAR T cell and other adoptive cell therapies to improve the survival and persistence of the infused cells.
- T cell engagers
-
(TCEs). Therapeutic molecules that simultaneously bind T cells via CD3 and target cells to more readily induce T cell-mediated cytotoxicity, using formats that range from small bispecific proteins (such as BiTEs) to larger immunoglobulin-like constructs.
- Tolerance
-
A safeguarding property that prevents the immune system from mounting responses to self-derived antigens, which is achieved through mechanisms that inactivate or eliminate autoreactive T cells and B cells.
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.
About this article
Cite this article
Zou, A.E., Kongthong, S., Mueller, A.A. et al. Fibroblasts in immune responses, inflammatory diseases and therapeutic implications. Nat Rev Rheumatol 21, 336–354 (2025). https://doi.org/10.1038/s41584-025-01259-0
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41584-025-01259-0
This article is cited by
-
Killing arthritogenic fibroblast-like synoviocytes: an example using cytotoxic aptamers binding nucleolin
Arthritis Research & Therapy (2025)
