Mechanistic insight of interleukin-9 induced osteoclastogenesis

• Published in: Immunology 2023-07, Vol.169 (3), p.309-322
• Main Authors: Chakraborty, Sushmita, Schneider, Jakob, Mitra, Dipendra Kumar, Kubatzky, Katharina F
• Format: Article
• Language: English
• Subjects: Animals; Arthritis; Arthritis, Rheumatoid - metabolism; Bone diseases; Bone growth; Bone marrow; Cell Differentiation; Cells, Cultured; Cytokines; Extracellular signal-regulated kinase; Inflammatory diseases; Interleukin-17 - metabolism; Interleukin-9 - metabolism; Interleukins; Lymphocytes; Lymphocytes T; MAP kinase; Mice; NF-κB protein; Osteoclastogenesis; Osteoclasts; Osteogenesis; Osteoprogenitor cells; Pathogenesis; Precursors; Psoriatic arthritis; RANK Ligand - metabolism; Rheumatoid arthritis; Signal Transduction; Signaling; Stat3 protein
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13630

Interleukin (IL)-9 is an emerging player in the pathogenesis of various chronic inflammatory diseases including bone disorders like rheumatoid arthritis (RA) and psoriatic arthritis. Recently, IL-9 was shown to enhance the osteoclast formation and their function in RA. However, the mechanisms by which IL-9 influences osteoclastogenesis are not known. Therefore, in this study we aimed to unravel the direct and indirect ways by which IL-9 can influence osteoclast formation. We used mouse bone marrow precursor cells for checking the effect of IL-9 on osteoclast differentiation and its function. Next, IL-9 induced signalling pathway were checked in the process of osteoclastogenesis. T cells play an important role in enhancing osteoclastogenesis in inflammatory conditions. We used splenic T cells to understand the impact of IL-9 on the functions of T effector (Teff) and regulatory T (Treg) cells. Furthermore, the effect of IL-9 mediated modulation of the T cell response on osteoclasts was checked using a coculture model of T cells with osteoclast precursors. We showed that IL-9 enhanced osteoclast formation and its function. We found that IL-9 activates STAT3, P38 MAPK, ERK1/2, NFκB and we hypothesize that it mediates the effect on osteoclastogenesis by accelerating mitochondrial biogenesis. Additionally, IL-9 was observed to facilitate the functions of pro-osteoclastogenic IL-17 producing T cells, but inhibits the function of anti-osteoclastogenic Treg cells. Our observations suggest that IL-9 can influence osteoclastogenesis directly by modulating the signalling cascade in the precursor cells; indirectly by enhancing IL-17 producing T cells and by reducing the functions of Treg cells.