Dual effect of IL‐7/IL‐7R signalling on the osteoimmunological system: a potential therapeutic target for rheumatoid arthritis

Abstract

The IL‐7/IL‐7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL‐7/IL‐7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and therefore ameliorate RA. Firstly, collagen‐induced arthritis (CIA) mice were administered with IL‐7Rα‐target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL‐7/IL‐7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL‐7, a STAT5 inhibitor or supernatants from T cells. The results showed that the IL‐7/IL‐7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL‐induced manner. We applied flow cytometry to analyse the effect of IL‐7 on T‐cell RANKL expression and found that IL‐7/IL‐7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL‐7/IL‐7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA.

Exploring the causal relationship between 91 inflammatory cytokines and two subtypes of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study

“…This leads to the generation of in ammatory microenvironment, initiating and promoting the development of RA [43]. Hence, IL-7 is considered as a new therapeutic target [5,[43][44][45]. Our research once again provides theoretical support for these perspectives about IL-7 (OR = 1.23, 95%CI = 1.05-1.43, p = 0.009, FDR = 0.195).…”

The Notch1 signaling pathway directly modulates the human RANKL-induced osteoclastogenesis

“…The binding of IL7 ligand to IL7R activates two main pathways including the Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and phosphoinositide-3 kinase (PI3K)/Akt, leading cell survival and development 36 , 37 , 47 , 49 – 51 . Notably our scRNA-seq data suggest that JAK/STAT signaling pathway is enriched at the early stage of RANKL-induced osteoclastogenesis (Fig.…”

“…Interestingly, recent studies indicate that JAK/STAT inhibitors, such as tofacitinib, significantly moderate the symptoms of rheumatoid arthritis and reduce the progression of osteoclasts as well as structural joint damage 57 . Moreover, it was reported that IL-7 contributes to inflammation and tissue destruction in patients with rheumatoid arthritis in a unique manner 37 and the blockade of IL-7/IL-7R signaling pathway protected collagen-induced arthritis (CIA) mice from bone degradation 51 . Taken together, these results support the therapeutic role of Notch1/IL7R axis in osteoclast-related diseases.…”

Advances in the research on myokine-driven regulation of bone metabolism

“…Several recent studies have suggested that the IL-7/IL-7R pathway has dual regulatory effects on osteoclasts. As a bone growth factor, IL-7 promotes osteoclast differentiation by increasing the expression of RANKL, a key T cell source; however, IL-7 blocks osteoclast differentiation by directly inhibiting the STAT5 pathway in the RANKL-induced system [ 81 , 82 ]. IL-7 may also suppress the bait receptor of RANKL, OPG to promote osteoclastogenesis and mediate estrogen-induced bone loss [ 83 ].…”