FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

Guo, Dong; Lin, Chuangxin; Lu, Yuheng; Guan, Hong; Qi, Weizhong; Shao, Yan; Zeng, Chun; Zhang, Rongkai; Zhang, Haiyan; Bai, Xia; Cai, Daozhang

doi:10.1038/s41413-022-00211-2

Cited by 41 publications

(31 citation statements)

References 59 publications

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“…In addition, macrophages can secrete a large number of cytokines and differentiate into pro-in ammatory M1 subtypes in the synovitis environment. These cytokines can further lead to joint destruction through neutrophil recruitment and T cell activation [21]. However, early RA is often di cult to diagnose because of its atypical clinical symptoms and lack of speci c serum diagnostic markers [22].…”

Section: Discussionmentioning

confidence: 99%

New classification of rheumatoid arthritis based on immune cells and clinical characteristics

Wang

Zhou²,

Xue

2023

Preprint

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Background Rheumatoid arthritis (RA) is a chronic systemic immune disease characterized by joint synovitis, but the specific etiology is unknown, and the characteristic serum diagnostic markers are also lacking. Methods First, we obtained the gene expression profile of synovium to evaluate the infiltration of immune cells in synovium, and screened the differentially expressed immune related genes for enrichment analysis. Subsequently, we classified RA into three subtypes by unsupervised clustering of serum gene expression profiles based on immune enrichment scores. Then, the enrichment and clinical characteristics of different subtypes were analyzed. Finally, according to the infiltration of different subtypes of immune cells, diagnostic markers were screened and verified by qRT-PCR. Results C1 subtype is related to the increase of neutrophils, CRP and ESR, and joint pain is more significant in patients. C2 subtype is related to the expression of CD8+T cells and Tregs, and patients have mild joint pain symptoms. The RF value of C3 subtype is higher, and the expression of various immune cells is increased. The function of this subtype is enriched in a variety of immune system diseases. T cells CD4, NK cells activated, macrophages M1 and neutrophils are immune cells significantly infiltrated in synovium and serum of RA patients. IFNGR1, TRAC, IFITM1 can be used as diagnostic markers of different subtypes. Conclusion In this study, RA patients were divided into different immune molecular subtypes based on gene expression profile, and immune diagnostic markers were screened, which provided a new idea for the diagnosis and treatment of RA.

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Section: Discussionmentioning

confidence: 99%

New classification of rheumatoid arthritis based on immune cells and clinical characteristics

Wang

Zhou²,

Xue

2023

Preprint

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“…Not only mechanical stress, but also synovitis, especially M1 macrophage polarization, received increasing attention [ 45 ]. According to clinical surveys and empirical findings, M1 macrophages are thought to be responsible for OA progression, including osteophyte generation and synovitis [ 46 , 47 , 48 ]. As a result, treatment techniques aimed at reducing the number of M1 macrophages or shifting M1 macrophages to M2 macrophages have been proposed as a way to attenuate OA progression.…”

Section: Discussionmentioning

confidence: 99%

Blocking TRPV4 Ameliorates Osteoarthritis by Inhibiting M1 Macrophage Polarization via the ROS/NLRP3 Signaling Pathway

Sun

et al. 2022

Antioxidants

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Osteoarthritis (OA) is a low-level inflammatory disease in which synovial macrophage M1 polarization exacerbates the progression of synovitis and OA. Notedly, the ROS (reactive oxygen species) level in macrophages is intimately implicated in macrophage M1 polarization. TRPV4 (transient receptor potential channel subfamily V member 4), as an ion channel, plays a pivotal role in oxidative stress and inflammation. In this study, we investigated the role of TRPV4 in OA progression and M1 macrophage polarization. Male adult Sprague–Dawley (SD) rats underwent a medial meniscus radial transection operation to create an OA model in vivo and RAW 264.7 cells were intervened with 100 ng/mL LPS (lipopolysaccharide) to induce M1-polarized macrophages in vitro. We demonstrated that the infiltration of M1 synovial macrophages and the expression of TRPV4 were increased significantly in OA synovium. In addition, intra-articular injection of HC067074 (a specific inhibitor of TRPV4) alleviated the progression of rat OA and significantly decreased synovial macrophage M1 polarization. Further mechanisms suggested that ROS production by M1 macrophages was decreased after TRPV4 inhibition. In addition, NLRP3 (pyrin domain containing protein 3) as a downstream effector of ROS in M1-polarized macrophage, was significantly suppressed following TRPV4 inhibition. In conclusion, this study discovered that inhibition of TRPV4 delays OA progression by inhibiting M1 synovial macrophage polarization through the ROS/NLRP3 pathway.

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“…Recent advances revealed that enhancing the expression of PPARg could attenuate disease manifestations (37). The adipokine fatty acid binding protein 4 (FABP4), which is an increased expression in RA serum and synovial tissues (38)(39)(40), plays an important role in the regulation of inflammation. Guo et al found that inhibition of FABP4 expression in macrophages could alleviate RA synovitis, angiogenesis, and cartilage degeneration (40).…”

Section: Discussionmentioning

confidence: 99%

“…The adipokine fatty acid binding protein 4 (FABP4), which is an increased expression in RA serum and synovial tissues (38)(39)(40), plays an important role in the regulation of inflammation. Guo et al found that inhibition of FABP4 expression in macrophages could alleviate RA synovitis, angiogenesis, and cartilage degeneration (40). Studies of transcriptomes of epithelial cell-specific NFIL3 knockout mice showed declined FABP4 expression, suggesting a positive regulatory relationship (41).…”

Section: Discussionmentioning

confidence: 99%

NFIL3 and its immunoregulatory role in rheumatoid arthritis patients

Zheng

Chen

et al. 2022

Front. Immunol.

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Nuclear-factor, interleukin 3 regulated (NFIL3) is an immune regulator that plays an essential role in autoimmune diseases. However, the relationship between rheumatoid arthritis (RA) and NFIL3 remains largely unknown. In this study, we examined NFIL3 expression in RA patients and its potential molecular mechanisms in RA. Increased NFIL3 expression levels were identified in peripheral blood mononuclear cells (PBMCs) from 62 initially diagnosed RA patients and 75 healthy controls (HCs) by quantitative real-time PCR (qRT-PCR). No correlation between NFIL3 and disease activity was observed. In addition, NFIL3 expression was significantly upregulated in RA synovial tissues analyzed in the Gene Expression Omnibus (GEO) dataset (GSE89408). Then, we classified synovial tissues into NFIL3-high (≥75%) and NFIL3-low (≤25%) groups according to NFIL3 expression levels. Four hundred five differentially expressed genes (DEGs) between the NFIL3-high and NFIL3-low groups were screened out using the “limma” R package. Enrichment analysis showed that most of the enriched genes were primarily involved in the TNF signaling pathway via NFκB, IL-17 signaling pathway, and rheumatoid arthritis pathways. Then, 10 genes (IL6, IL1β, CXCL8, CCL2, PTGS2, MMP3, MMP1, FOS, SPP1, and ADIPOQ) were identified as hub genes, and most of them play a key role in RA. Positive correlations between the hub genes and NFIL3 were revealed by qRT-PCR in RA PBMCs. An NFIL3-related protein–protein interaction (PPI) network was constructed using the STRING database, and four clusters (mainly participating in the inflammatory response, lipid metabolism process, extracellular matrix organization, and circadian rhythm) were constructed with MCODE in Cytoscape. Furthermore, 29 DEGs overlapped with RA-related genes from the RADB database and were mainly enriched in IL-17 signaling pathways. Thus, our study revealed the elevated expression of NFIL3 in both RA peripheral blood and synovial tissues, and the high expression of NFIL3 correlated with the abnormal inflammatory cytokines and inflammatory responses, which potentially contributed to RA progression.

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FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

Cited by 41 publications

References 59 publications

New classification of rheumatoid arthritis based on immune cells and clinical characteristics

New classification of rheumatoid arthritis based on immune cells and clinical characteristics

Blocking TRPV4 Ameliorates Osteoarthritis by Inhibiting M1 Macrophage Polarization via the ROS/NLRP3 Signaling Pathway

NFIL3 and its immunoregulatory role in rheumatoid arthritis patients

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