Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation in the joints, leading to pain, stiffness, and progressive disability. It affects nearly 2% of the global population, with a higher prevalence in women. The disease results from a combination of genetic, environmental, and immune factors, triggering chronic inflammation. Key contributors include pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, along with T cells and B cells that drive joint destruction. Over time, this inflammatory process weakens tendons and ligaments, leading to severe functional impairment. Despite extensive research, the exact cause of RA remains unclear, making treatment complex and often focused on symptom management.
Recent studies highlight the role of semaphorins, a group of signaling molecules known for regulating endothelial function, in the progression of RA. Semaphorins contribute to pathological angiogenesis, a key factor in sustaining joint inflammation. Their involvement in immune modulation suggests they may influence disease severity and progression. Research into their mechanisms could provide insights into novel therapeutic approaches, potentially leading to new treatments for RA. This review explores the impact of semaphorins on RA and their potential role in developing targeted therapies.
Semaphorins
Semaphorins are a group of 30 glycoproteins essential for cellular development and immune regulation. They are divided into eight classes based on structure and species origin, with classes 3–7 found in vertebrates. These proteins play a key role in cardiovascular development, autoimmune diseases, and nervous system function by guiding axon and dendrite growth. In the immune system, semaphorins act as signaling ligands, influencing cell morphology and motility.
Semaphorin signaling is mediated through neuropilins and plexins, which act as transmembrane receptors (Figure 1). Their interaction triggers intracellular pathways linked to RA progression. Research shows increased levels of plexin C1 and β1-integrin, key SEMA7A receptors, in RA patients, indicating their role in immune dysfunction. Understanding these mechanisms could lead to new RA therapies.
Table 2. Deceased incidence and cardiovascular risk factor prevalence among deceased.
Semaphorins regulate immune cells invading synovial tissue and are produced by endothelial cells, T cells, B cells, macrophages, and dendritic cells. Activated T cells and macrophages release proangiogenic cytokines like IL-6, TNF-α, and IL-17, which contribute to RA pathogenesis. These cytokines activate rheumatoid arthritis synovial fibroblasts (RASFs), intensifying inflammation. Semaphorins modulate immune responses, playing a key role in autoimmune diseases like RA.
Each semaphorin class functions uniquely (Figure 2). SEMA3A (Class 3) reduces RA inflammation by inducing IL-10 and downregulating IL-17 and IFN-γ. Class 4 semaphorins, linked to swollen joint markers, act as immunostimulators. SEMA5A (Class 5) promotes proinflammatory factors and inhibits cell death. SEMA7A (Class 7) enhances cytokines like TNF-α, IL-6, and IL-17, accelerating RA progression. Figure 2 illustrates semaphorins’ role in RA pathogenesis.
Figure 2. The role of semaphorins in the pathogenesis of RA (29–33). Interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor–alpha (TNF-α), vascular endothelial growth factor (VEGF), interferon-gamma (IFN-γ), neuropilin-1/2 (NRP-1/2), metalloproteinases (MMPs), interleukin 17 (IL-17), synovial fibroblasts (SFs).
Angiogenesis and Destruction of the Synovial Joint
Angiogenesis plays a crucial role in the early stages of RA, driving synovial tissue proliferation and pannus formation. Semaphorins regulate angiogenesis, either promoting or inhibiting the process, as seen in cancer studies. During RA inflammation, RASFs invade and destroy cartilage and bone, while synovial fibroblasts (SFs) and fibroblast-like synoviocytes (FLSs) release MMPs and cytokines that degrade the extracellular matrix. Inflammation fuels angiogenesis, worsening RA progression. Targeting angiogenesis could help reduce inflammation and slow disease progression.
Two theories explain angiogenesis in RA. The first suggests inflammation triggers angiogenesis via hypoxia-induced VEGF release, while the second proposes angiogenesis precedes leukocyte infiltration, intensifying inflammation. SEMA3A reduces angiogenesis in asthma models and may have similar effects in RA. SEMA3E decreases VEGF levels, while SEMA3F and SEMA3E inhibit endothelial migration and adhesion. However, some semaphorins, like SEMA4A, SEMA4D, and SEMA7A, promote angiogenesis. Understanding semaphorins’ role in angiogenesis could lead to novel autoimmune disease treatments.
The Possible Use of Semaphorins in RA Treatments
Current pharmacological treatments for rheumatoid arthritis (RA) include Janus kinase (JAK) inhibitors (e.g., baricitinib, tofacitinib), disease-modifying antirheumatic drugs (DMARDs) like methotrexate (MTX) and leflunomide, and anti-cytokine drugs (e.g., adalimumab, infliximab). MTX is the most commonly used drug, often as a first choice, followed by sulfasalazine or leflunomide. Research into the use of semaphorins as potential therapeutic targets for RA is still in early stages, and their efficacy remains to be fully established.
Class 3 Semaphorins and RA
Class 3 semaphorins, initially thought to inhibit VEGF-induced angiogenesis, are now recognized for their involvement in pathological angiogenesis and vessel remodeling in RA (Figure 3). In patients with RA, the expression of class 3 semaphorins, such as SEMA3B and SEMA3F, is significantly reduced in synovial tissue. Studies suggest that SEMA3A acts as an immunoregulator, as it reduces inflammatory cytokines and improves survival in animal models of autoimmune diseases like lupus nephritis. Additionally, a truncated version of SEMA3A has shown potential in promoting regulatory cytokine production, further supporting its possible therapeutic role in maintaining immune homeostasis.
Figure 3. SEMA3A importance as an immunoregulator
Class 3 semaphorins participate in FLS-mediated joint destruction and regulate the invasive activity of FLSs. Reducing SEMA3B and SEMA3F expression through initial inflammatory cues in early arthritis may have a crucial impact on disease development by suppressing FLSs. The involvement of SEMA3B and SEMA3F in RA is related to FLS-mediated joint destruction and MMP production. However, class 3 semaphorins do not regulate FLS proliferation and viability. The effects of SEMA3A, SEMA3B, and SEMA3F on RA FLSs are shown in Figure 4
Figure 4. The effects of class 3 semaphorins on rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs). Abbreviations: foetal bovine serum (FBS); platelet-derived growth factor (PDGF).
Several studies on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA), and control groups found a significant decrease in SEMA3A levels in the SLE and RA groups compared to the control and OA groups. There was a negative correlation between serum SEMA3A levels and disease activity markers like erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Disease Activity Score 28 (DAS28). However, some studies, like one by Gao et al., reported contradictory results.
SEMA3A expression was also found to be decreased in RA patients’ serum, possibly due to its solubility and lower expression in joints. The balance between SEMA3A and VEGF may regulate key RA processes such as inflammation, angiogenesis, and synovial cell proliferation. SEMA3A administration can attenuate joint tissue damage by inhibiting VEGF-induced processes like endothelial cell proliferation, migration, and fibroblast-like synoviocyte (FLS) invasion. Additionally, SEMA3A levels in urine are a strong disease activity marker, especially in SLE.
SEMA3B, SEMA3F, and SEMA3G levels negatively correlated with RA disease activity markers such as DAS28, ESR, and CRP. These class 3 semaphorins’ reduced expression in synovial tissue was linked to disease activity parameters. FLSs in inflamed synovial tissues expressed SEMA3B and SEMA3F, while monocytes or macrophages did not. However, a different study on a mouse model and RA patients indicated that SEMA3G exacerbates joint inflammation by promoting macrophage proliferation and migration. The inhibition of FLS activation by SEMA3B and SEMA3F is thought to involve the ERK and Rac1 signaling pathways, which are elevated in the synovial tissues of RA patients
Class 4 Semaphorins and RA
SEMA4D plays key roles in RA, involved in angiogenesis and immune activation. Elevated SEMA4D levels in the serum and synovial fluid of RA patients correlate inversely with CRP and DAS28. It interacts with ADAMTS-4, an enzyme responsible for cartilage degradation. Soluble SEMA4D increases TNF-α and IL-6 production, promoting osteoclastogenesis and inflammatory processes. Anti-SEMA4D antibodies reduce TNF-α and IL-6 levels, decreasing pathological angiogenesis and synovial inflammation. SEMA4D may predict radiographic progression in RA.
Class 4 semaphorins, including SEMA4A, are linked to RA disease activity, with higher levels in patients with active RA (DAS28 > 5.1). Elevated SEMA4A levels correlate with DAS28, swollen joint count, and MMP activity, promoting RASF invasion and inflammation. SEMA4A competes with SEMA4D for the plexin D1 receptor, having opposite effects on RA activity. It is higher in RA compared to OA, and even more so in SLE patients. SEMA4A levels predict treatment failure in RA patients, with higher specificity when combined with DAS28-CRP or Doppler ultrasound. SEMA4G has been linked to certolizumab pegol response due to a significant SNP near its gene.
Class 5 Semaphorins and RA
SEMA5A is elevated in the serum of SLE and RA patients, particularly in synovial macrophages (SMs) from RA patients compared to OA patients. It plays a significant role in RA pathogenesis by promoting pannus formation, T cell and NK cell activation, and the release of inflammatory factors like IL-6, IL-8, and MMPs. SEMA5A binds to plexin-A1 and plexin-B3 receptors, stimulating synovial fibroblasts (SFs) and reducing SF apoptosis and ferroptosis. It also activates the PI3K/AKT/mTOR pathway, increasing GPX4 levels and suppressing ferroptosis.
SEMA5A also contributes to angiogenesis. The TSP-1 domain is crucial for its pathological role in RA, as its absence reduces angiogenesis and pannus damage, while increasing anti-inflammatory IL-10 levels. Additionally, SEMA5A enhances T cell and NK cell levels, with IL-2 and IL-15 amplifying this effect. Blocking SEMA5A using the SYD12-12 antibody in a mouse model halted disease progression, including inhibiting angiogenesis and bone destruction, demonstrating its therapeutic potential
Class 7 Semaphorins and RA
SEMA7A plays a key role in RA development by mediating immune responses, particularly through its interaction with T cells and monocytes. Blocking SEMA7A-β1 signaling reduces RA symptoms in experimental models. It regulates cytokine secretion, enhancing TNF-α and IL-6 production, both crucial in RA progression. Studies show a significant correlation between soluble SEMA7A levels in serum and synovial fluid and RA indicators like DAS28, CRP, and RF. SEMA7A also upregulates cytokines like IFN-γ, IL-17, and Th17/Tc17, and its effects are attenuated by blocking β1-integrin, which activates focal adhesion kinase (FAK) in monocytes. SEMA7A could serve as a therapeutic target and marker for RA progression.
Conclusion
RA is a chronic autoimmune disease that causes inflammation in joint tissues, leading to abnormal immune activation and clinical changes. The synovial membrane becomes infiltrated with B cells, T cells, and monocytes, triggering angiogenesis and the activation of endothelial cells and synoviocytes. This results in cartilage damage and bone resorption. As RA progresses, causing disability, researchers are exploring mediators involved in the disease’s pathogenesis that could serve as markers and therapeutic targets. Recent studies highlight the significant role of semaphorins, particularly class 3–7, in RA inflammation and their potential as new therapy targets. Animal models show promise, but further clinical research is needed to fully understand semaphorins’ role in RA and develop new treatments.
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