Follistatin-like protein 1 promotes inflammatory reactions in nucleus pulposus cells by interacting with the MAPK and NFκB signaling pathways

Liu

et al. 2020

Preprint

Background Asthma is a common respiratory disease characterized by chronic airway inflammation. As a novel inflammatory mediator, follistatin-like protein 1 (FSTL1) can activate immune reaction, suggesting that it may contribute to inflammatory disorders such as asthma. Besides, there are growing evidences that nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) / Interleukin (IL)-1β axis participates in asthma. In this study, we investigated the role of FSTL1 in allergic airway inflammation and its underlying mechanism of activating NLRP3 inflammasome. Methods Circulating FSTL1 and IL-1β levels were quantified in serum of asthmatic patients and controls. Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/- ) and control group were assessed after the experimental treatment. The effects of FSTL1 on NLRP3 inflammasome were also tested in primary macrophages of mice in vitro. Results The concentration of FSTL1 and IL-1β in serum of asthmatic patients were elevated compared with controls and were positively correlated. FSTL1 deficiency ameliorated infiltration of inflammatory cells,corresponding pathological changes,cytokine responses (IL-1β, IL-5,IL-13), mucous hypersecretion and hyper-responsiveness of airway after Ovalbumin (OVA) exposure in the mouse model. Additionally, inhibition of NLRP3 with MCC950 attenuated FSTL1-induced activation of NLRP3 inflammasome and airway inflammation in vivo and vitro. Conclusions Our data showed that FSTL1 played an important role in allergic airway inflammation by activating NLRP3 inflammasome, providing the possibility that FSTL1 could be applied as a therapeutic strategy on asthma.

“…However, this airway inflammation was significantly inhibited by pre-injection of MCC950. [36], [37]. In our study, we demonstrated the pro-inflammatory role of FSTL1 in asthma.…”

Section: Mcc950 Treatment Attenuated Fstl1-induced Activation Of Nlrp3supporting

confidence: 64%

FSTL1 aggravates OVA-induced allergic airway inflammation by activating NLRP3 inflammasome

Liu

et al. 2020

Preprint

“…FSTL1 is known to drive pathology in inflammatory disease settings in mouse models, particularly arthritis (41)(42)(43)(44)(45)(46)(47). Among its various activities, it has been reported to promote inflammatory cytokine production, including IL-1β, from macrophages and fibroblasts (41,47,48). While FSTL1 mRNA was significantly elevated in CLD Linear regression of the top 12 genes that most strongly correlate with ELF score (r 2 value of 0.39 or more), showing gene expression as an independent variable and ELF score as a dependent variable.…”

Section: Resultsmentioning

confidence: 99%

“…This approach revealed 12 such genes ( Figure 6D), 10 of which encoded extracellular proteins (Table 3). Since inflammation, associated cell death, and aberrant wound healing are central to the progression of liver fibrosis in NAFLD (78), we pursued FSTL1 as a steatosis-linked gene, because of its strong links to both inflammation and fibrosis (40,41,(43)(44)(45)79). FSTL1 is a secreted glycopro- Supplemental Table 1 for details of the patient cohort; n = 35; detectable levels in 9 patients; horizontal bars indicate mean ± SEM; circles, early stages; triangles, advanced stages).…”

Section: List Of 11 Degs (With 25-fold Difference In Expression Bementioning

confidence: 99%

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes

Ramnath¹,

Irvine²,

Lukowski

et al. 2018

JCI Insight

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

J Cellular Molecular Medi

“…33 Previous reports showed that FSTL1 stimulate the expression of MMPs in synoviocytes and nucleus pulposus cells. 14,16 Therefore, in this study, we investigated whether FSTL1 affects the expression of MMPs in chondrocytes. Our results showed that FSTL1 significantly increased the expression of MMP-1 and MMP-13 in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Follistatin‐like protein 1 (FSTL1) promotes chondrocyte expression of matrix metalloproteinase and inflammatory factors via the NF‐κB pathway

Sun

et al. 2019

Background The expression of follistatin‐like protein 1 (FSTL1) is closely associated with diseases of the musculoskeletal system. However, despite being a well characterized inflammatory mediator, the effects of FSTL1 on chondrocytes are not completely understood. In this study, we investigated the effects of FSTL1 on the expression of inflammatory and catabolic factors in rat chondrocytes. Methods Rat chondrocytes were treated directly with various concentrations of FSTL1 in vitro. The levels of matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‐2, interleukin (IL)‐1β, tumour necrosis factor (TNF)‐α and IL‐6 were measured by polymerase chain reaction, ELISA and Western blotting. In addition, activation of the nuclear factor kappa B (NF‐κB) pathway was explored to identify potential regulatory mechanisms. Results Follistatin‐like protein 1 directly increased the expression of MMP‐1, MMP‐13, iNOS, COX‐2, IL‐1β, TNF‐α and IL‐6 at both gene and protein level in a dose‐dependent manner. Activation of NF‐ κB and phosphorylation of p65 were also promoted by FSTL1 stimulation. Conclusions Follistatin‐like protein 1 exerts pro‐inflammatory and catabolic effects on cultured chondrocytes via activation of the NF‐κB signalling pathway. FSTL1 may therefore be a target in the treatment of OA.