The Notch signaling-regulated angiogenesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials

Abstract

Angiogenesis plays a key role in the pathological process of inflammation and invasion of the synovium, and primarily drives the progression of rheumatoid arthritis (RA). Recent studies have demonstrated that the Notch signaling may represent a new therapeutic target of RA. Although the Notch signaling has been implicated in the M1 polarization of macrophages and the differentiation of lymphocytes, little is known about its role in angiogenesis in RA. In this review, we discourse the unique roles of stromal cells and adipokines in the angiogenic progression of RA, and investigate how epigenetic regulation of the Notch signaling influences angiogenesis in RA. We also discuss the interaction of the Notch-HIF signaling in RA's angiogenesis and the potential strategies targeting the Notch signaling to improve the treatment outcomes of RA. Taken together, we further suggest new insights into future research regarding the challenges in the therapeutic strategies of RA.

Keywords: Notch signaling; adipokines; angiogenesis; epigenetic regulation; rheumatoid arthritis.

Figure 1

The role of stromal cells and adipokines in RA angiogenesis. Innate immune cells (including dendritic cells, cells-Myeloid-derived suppressor cells, and macrophages), adaptive immune cells (including CD4⁺ T cells and CD8⁺ T cells), vascular endothelial cells, and adipokines (including fatty acid-binding protein 4 (FABP4), adiponectin, secreted protein acidic and rich in cysteine (SPARC)) greatly influence the progression of angiogenesis in the RA microenvironment. The cross-talk interactions of stromal cells and adipokines form a continuous cycle, further deteriorating RA.

Figure 2

The dual inflammatory actions (pro- and anti-) of MDSCs in RA. (A) MDSCs promote the response of Th17 cells via IL-1β signaling and also differentiate into osteoclasts by interacting with Th17 cells and upregulating nuclear factor κβ ligand-RANK signaling, potentiating the inflammatory response. MDSCs may suppress Treg cell responses. (B) MDSCs inhibit the expression of DCs maturation biomarkers (CD80, CD86, MHC-II), suppress Th17 cell responses, and reduce the pro-inflammatory factors (TGF-α, GM-CSF) secreted by macrophages. MDSCs also potentiate Treg cells to depress the progress of synovitis.

Figure 3

The role of macrophage polarization in the evolution of angiogenesis in RA. Under the stimulation of various pathological factors, macrophages polarize into pro-inflammatory M1 macrophages and M2 macrophages involved in the resolution of inflammation. M2 macrophages mediate microRNAs, pro-angiogenic growth factors, and angiogenic CXC chemokines to establish the cell–cell interaction with endothelium, promoting the ECs’ proliferation and potentiating the formation of the vascular network.

Figure 4

Crosstalk between FLSs and ECs in angiogenesis of RA. During the formation of pannus in the synovium tissue of RA, FLSs promote resident macrophage polarization, accelerating the secretion of pro-inflammatory mediators and pro-angiogenic factors. The aberrant proliferation of FLSs amplifies the ECs response through the activation of inflammation. FAP-α recruits and co-interacts with abnormal cells to induce local angiogenesis. In addition, ECs provide the pro-inflammatory phenotype of FLS to foster the development of synovitis.

Figure 5

The canonical Notch signaling pathway. In the signal-receiving cell, Notch precursors are glycosylated by the endoplasmic reticulum and undergo S1 cleavage in the Golgi. The mature Notch receptors are transported into the cell membrane. Canonical Notch ligands bind to the Notch receptors, and Notch signaling induces cleavage at the S2 site. Then S3-cleavage is catalyzed by γ-secretase, causing the release of NICD. The NICD is transferred into the nucleus, where it interacts with transcriptional regulators and the coactivator to promote the transcription of Notch downstream target genes.