IL‑1β increases the expression of inflammatory factors in synovial fluid‑derived fibroblast‑like synoviocytes via activation of the NF‑κB‑mediated ERK‑STAT1 signaling pathway

Yang, Jie; Wang, Junhu; Liang, Xiaojun; Zhao, Hongmou; Lü, Jun; Ma, Qiang; Jing, Bingfei; Tian, Feng

doi:10.3892/mmr.2019.10759

Cited by 14 publications

(23 citation statements)

References 42 publications

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“…Furthermore, our preliminary data showing activation of STAT1 in CIA SFs suggest coupling to STAT1 in conjunction with STAT3 signalling could explain the differential effects of ARNO in healthy and CIA SFs. Interestingly, simultaneous activation of NF-κB and STAT3 was found to enhance the inflammatory responses of non-immune cells ( 69 ) whilst an IL-1β activated ERK/STAT1 signaling pathway was proposed to promote NF−κB−mediated cytokine secretion in rat synovial fibroblasts ( 70 ). Therefore, ARNO could modulate SF-dependent inflammation by affecting the balance of STAT1/STAT3-NFκB pathways, a hypothesis we are currently investigating.…”

Section: Discussionmentioning

confidence: 99%

Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts

et al. 2022

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The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6 that has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process has previously been unexplored but we hypothesized that the pro-inflammatory milieu of inflamed joints locally induces activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway which can be rapidly activated by IL-1β. Such signalling promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating their precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.

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Section: Discussionmentioning

confidence: 99%

Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts

et al. 2022

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“…In the next step, we investigated whether improvement of mitochondrial function will reduce the synthesis and expression of pro-inflammatory mediators in recipient FLS. IL1B plays crucial role in the progression of arthritis via modulation of NF-κB-mediated ERK/STAT signalling pathway while its inhibition decrease inflammation and facilitate the treatment of disease [ 4 ]. The present results suggested that mitotransfer decrease IL1B on the mRNA and protein expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…In the course of SI, FLSs are losing their protective and pro-regenerative cytological features, and become highly proliferative and metabolically active cells initiating various stress signaling pathways. Activated FSL have been shown to produce a broad range of proinflammatory cytokines including IL-1β, IL-6, IL-9, IL-15 or TNF-α while losing their immunomodulatory effect [ 4 ]. Recent data have demonstrated that activated FLS additionally release a wide plethora of caspases and metalloproteinases, that initiate unreversible joint degenerative changes.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria transfer restores fibroblasts-like synoviocytes (FLS) plasticity in LPS-induced, in vitro synovitis model

Kornicka

Groborz²,

Lynda

et al. 2022

Cell Commun Signal

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Background Synovitis (SI) is one of the most common and serious orthopedic diseases in horses of different age, breed and sex, which contributes to the development of osteoarthritis. The burden of SI includes economic loss and represents a real challenge for current veterinary health care. At the molecular level, fibroblasts-like synoviocytes (FLS) are recognized as major cell populations involved in SI pathogenesis. In the course of SI, FLSs are losing their protective and pro-regenerative cytological features, become highly proliferative and initiate various stress signaling pathways. Methods Fibroblast-like synoviocytes were treated with LPS in order to generate SI in vitro model. Mitochondria were isolated from peripheral blood derived mononuclear cells and co-cultured with FLS. After 24 h of culture, cells were subjected to RT-qPCR, western blot, cytometric and confocal microscopy analysis. Results Mitochondrial transfer (MT) was observed in vitro studies using confocal microscopy. Further studies revealed, that MT to LPS-treated FLS reduced cell proliferation, modulated apoptosis and decreased inflammatory response. Overall, MT Resulted in the considerable recovery of recipient cells cytophysiological properties. Conclusions Presented data provides evidence that mitochondria transfersignificantly modulate FLS proliferative and metabolic activity through improved mitochondrial biogenesis and dynamics in activated FLS. Obtained results for the first time demonstrate that horizontal MT might be considered as a therapeutic tool for synovitis treatment; however, further clinical studies are strongly required.

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“…This effect is mediated almost completely by the proNGF present in SF, as the inhibition of proNGF binding to p75NTR led to an 80% reduction in IL-6 production. As it is well known that IL-1b enhances the expression levels of various inflammatory factors in RA-FLS through the activation of NF-kB/ERK/STAT1 axis, p38 mitogen-activated protein kinase (MAPK) and JUNK signaling pathways (22,32,33,47), we compared the effects of IL-1b and p75NTR neutralization on inflammatory cytokine production. We found that in RA-FLS the inhibition of p75NTR activation by LM11A-31 reduces the release of IL-6 to a similar extent as IL-1b inhibition by canakinumab.…”

Section: Discussionmentioning

confidence: 99%

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis

et al. 2022

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We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of proNGF on fibroblast-like synoviocytes (FLS), which play a central role in modulating local immune responses and in activating pro-inflammatory pathways. Using single cell RNA sequencing in synovial tissues from active and treatment-naïve rheumatoid arthritis (RA) patients, we demonstrated that p75NTR and sortilin, which form a high affinity receptor complex for proNGF, are highly expressed in PRG4pos lining and THY1posCOL1A1pos sublining fibroblast clusters in RA synovia but decreased in RA patients in sustained clinical remission. In ex vivo experiments we found that FLS from rheumatoid arthritis patients (RA-FLS) retained in vitro a markedly higher expression of p75NTR and sortilin than FLS from osteoarthritis patients (OA-FLS). Inflammatory stimuli further up-regulated p75NTR expression and induced endogenous production of proNGF in RA-FLS, leading to an autocrine activation of the proNGF/p75NTR pathway that results in an increased release of pro-inflammatory cytokines. Our data on the inhibition of p75NTR receptor, which reduced the release of IL-1β, IL-6 and TNF-α, further confirmed the key role of p75NTR activation in regulating inflammatory cytokine production. In a set of ex vivo experiments, we used RA-FLS and cultured them in the presence of synovial fluids obtained from arthritis patients that, as we demonstrated, are characterized by a high concentration of proNGF. Our data show that the high levels of proNGF present in inflamed synovial fluids induced pro-inflammatory cytokine production by RA-FLS. The blocking of NGF binding to p75NTR using specific inhibitors led instead to the disruption of this pro-inflammatory loop, reducing activation of the p38 and JNK intracellular pathways and decreasing inflammatory cytokine production. Overall, our data demonstrate that an active proNGF/p75NTR axis promotes pro-inflammatory responses in synovial fibroblasts, thereby contributing to chronic synovial inflammation, and point to the possible use of p75NTR inhibitors as a novel therapeutic approach in chronic arthritis.

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IL‑1β increases the expression of inflammatory factors in synovial fluid‑derived fibroblast‑like synoviocytes via activation of the NF‑κB‑mediated ERK‑STAT1 signaling pathway

Cited by 14 publications

References 42 publications

Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts

Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts

Mitochondria transfer restores fibroblasts-like synoviocytes (FLS) plasticity in LPS-induced, in vitro synovitis model

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis

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