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The function of eosinophils in bone remodelling

Subject Area Rheumatology
Immunology
Term from 2018 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 396348248
 
Final Report Year 2023

Final Report Abstract

Maintaining a healthy skeletal structure requires a delicate balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. However, this equilibrium can be disrupted by inflammation, such as in the case of rheumatoid arthritis (RA), which promotes the development of osteoclasts and leads to a decrease in bone mass and an increased risk of fractures. While the pro-osteoclastogenic effects of RA-associated immune cells and cytokines are well-documented, little is known about immune cells and mediators that inhibit osteoclast formation. Recent studies have suggested that type-2 immunity-related cytokines, which are highly secreted by eosinophils, can suppress osteoclast differentiation and function. Despite this evidence, the regulatory role of eosinophils in bone has not received much attention and requires further investigation. Our study has shown that eosinophils can effectively suppress osteoclast differentiation in vitro, likely through the release of soluble mediators, as evidenced by the fact that pure eosinophil supernatant had the same effect. These findings were further confirmed in an in vivo setting, as eosinophil-deficient mice displayed an osteoporosis-like bone phenotype with increased osteoclasts, while hyper-eosinophilic IL-5tg/4get mice exhibited high bone mass with impaired osteoclast activation. This indicates that eosinophils play a critical role in regulating physiological bone remodeling. We also investigated the role of eosinophils in arthritis-mediated bone erosion in synovial tissue. To do so, we combined two type-2 immune response-inducing models (helminth infection and eosinophilic asthma) with K/BxN serum-induced arthritis. Both models resulted in the accumulation of eosinophils in the synovium, which was accompanied by resolution of arthritis and reduced synovial inflammation and osteoclast-mediated bone erosion. Interestingly, these mice also had decreased osteophyte formation, indicating that eosinophils may also influence the regeneration of eroded articular bone. Single cell RNA sequencing and proteome profiling revealed that synovial eosinophils possess pro-resolving and osteo-protective properties, as compared to pro-inflammatory eosinophils located in the lungs. Mechanistically, these synovial eosinophils are recruited by systemic IL-5 that is produced by type-2 innate lymphoid cells in the lungs. Our findings highlight the beneficial effect of eosinophils during the resolution of inflammatory arthritis and the regeneration of eroded synovial bone. In humans, eosinophils were found to be predominantly present in the synovial tissue of RA patients in remission state. Despite this comprehensive characterization of the role eosinophils play during physiological and pathological bone resorption, there is still a need for additional research to elucidate the molecular mechanisms underlying their pro-resolving and osteoclast-suppressing functions.

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