Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin; Marshall, Jennifer L.; Rao, Deepak A.; Chang, Song Ho; Nguyen, Hung N.; Noss, Erika H.; Turner, Jason D.; Earp, Brandon E.; Blazar, Philip E.; Wright, John; Simmons, Barry P.; Donlin, Laura T.; Kalliolias, George D.; Goodman, Susan M.; Bykerk, Vivian P.; Ivashkiv, Lionel B.; Lederer, James A.; Hacohen, Nir; Nigrović, Peter A.; Filer, Andrew; Buckley, Christopher D.; Raychaudhuri, Soumya; Brenner, Michael B.

doi:10.1038/s41467-018-02892-y

Cited by 391 publications

(562 citation statements)

References 44 publications

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“…Although inflammatory cytokines and MMPs were mainly expressed in CD34 + and CD34 + THY1 − fibroblasts, respectively, in human RA synovium (Mizoguchi et al ., ), CD90.2 + FLS, known to be THY1 + , isolated from mouse knee joints showed increased inflammatory cytokine and MMP expression in our data.…”

Section: Discussionsupporting

confidence: 66%

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang

Kwon

Lee

et al. 2018

British J Pharmacology

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Background and Purpose3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in in vitro and in vivo models.Experimental ApproachThe anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes in vitro and an in vivo mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects in vitro. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.Key Results3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis via NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.Conclusions and Implications3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated via blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.

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Section: Discussionsupporting

confidence: 66%

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang

Kwon

Lee

et al. 2018

British J Pharmacology

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“…Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85]. Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85].…”

Section: Role Of Metabolism In Synovial Fibroblast Activation In Ramentioning

confidence: 99%

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Fearon

Hanlon

Wade

et al. 2018

Clinical and Experimental Immunology

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Rheumatoid arthritis is characterized by synovial proliferation, neovascularization and leucocyte extravasation leading to joint destruction and functional disability. The blood vessels in the inflamed synovium are highly dysregulated, resulting in poor delivery of oxygen; this, along with the increased metabolic demand of infiltrating immune cells and inflamed resident cells, results in the lack of key nutrients at the site of inflammation. In these adverse conditions synovial cells must adapt to generate sufficient energy to support their proliferation and activation status, and thus switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This alters redox-sensitive signalling pathways and also results in the accumulation of metabolic intermediates which, in turn, can act as signalling molecules that further exacerbate the inflammatory response. The RA synovium is a multi-cellular tissue, and while many cell types interact to promote the inflammatory response, their metabolic requirements differ. Thus, understanding the complex interplay between hypoxia-induced signalling pathways, metabolic pathways and the inflammatory response will provide better insight into the underlying mechanisms of disease pathogenesis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIESTranslating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experimental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity.

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“…However, fibroblasts are not a uniform population of cells, but rather are composed of functionally and phenotypically different subsets. Emerging evidence demonstrates that chronic inflammatory diseases, including rheumatoid arthritis, are associated with an imbalance in the ratio of different fibroblast subsets, and that those shifts may drive disease progression . The complexity of different fibroblast subsets in fibrotic diseases such as SSc is less well understood.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Soare

Györfi

Matei

et al. 2019

Arthritis & Rheumatology

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Objective Expression of dipeptidylpeptidase 4 (DPP‐4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP‐4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP‐4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods Expression of DPP‐4 in skin biopsy samples and dermal fibroblasts was analyzed by real‐time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP‐4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results The expression of DPP‐4 and the number of DPP‐4–positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)–dependent manner. DPP‐4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ‐induced ERK signaling. DPP4‐knockout mice were less sensitive to bleomycin‐induced dermal and pulmonary fibrosis (P < 0.0001 versus wild‐type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft‐versus‐host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion DPP‐4 characterizes a population of activated fibroblasts and shows that DPP‐4 regulates TGFβ‐induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well‐tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.

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Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis

Cited by 391 publications

References 44 publications

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

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