Downregulation of regulatory T cell function in patients with delayed fracture healing

Jiang, Hui; Ti, Yunfan; Wang, Yicun; Wang, Jun; Chang, MengHan; Zhao, Jianning; Sun, Guoqiang

doi:10.1111/1440-1681.12902

Cited by 14 publications

(8 citation statements)

References 21 publications

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“…An increasing amount of data are available about fracture healing that might be relevant in this context. 8,12,18,21 Both tendon and bone shafts need to have mesenchymal cells recruited to the site of injury from the peritendineum or the periosteum and activated. The initial inflammation is important for this process, similar in bone and tendon healing.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome

et al. 2018

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Background: The immune system reflects the microbiome (microbiota). Modulation of the immune system during early tendon remodeling by dexamethasone treatment can improve rat Achilles tendon healing. The authors tested whether changes in the microbiota could influence the effect of dexamethasone treatment. Hypothesis: A change in microbiome would influence the response to dexamethasone on regenerate remodeling, specifically tendon material properties (peak stress). Study Design: Controlled laboratory study. Methods: Specific opportunist and pathogen-free female rats were housed separately (n = 41) or together with specific pathogen-free rats carrying opportunistic microbes such as Staphylococcus aureus (n = 41). After 6 weeks, all co-housed rats appeared healthy but now carried S aureus. Changes in the gut bacterial flora were tested by API and RapID biochemical tests. All rats (clean and contaminated) underwent Achilles tendon transection under aseptic conditions. Flow cytometry was performed 8 days postoperatively on tendon tissue. Sixty rats received subcutaneous dexamethasone or saline injections on days 5 through 9 after transection. The tendons were tested mechanically on day 12. The predetermined primary outcome was the interaction between contamination and dexamethasone regarding peak stress, tested by 2-way analysis of variance. Results: Dexamethasone increased peak stress in all groups but more in contaminated rats (105%) than in clean rats (53%) (interaction, P = .018). A similar interaction was found for an estimate of elastic modulus ( P = .021). Furthermore, dexamethasone treatment reduced transverse area but had small effects on peak force and stiffness. In rats treated with saline only, contamination reduced peak stress by 16% ( P = .04) and elastic modulus by 35% ( P = .004). Contamination led to changes in the gut bacterial flora and higher levels of T cells (CD3+CD4+) in the healing tendon ( P < .05). Conclusion: Changes in the microbiome influence tendon healing and enhance the positive effects of dexamethasone treatment during the early remodeling phase of tendon healing. Clinical Relevance: The positive effect of dexamethasone on early tendon remodeling in rats is strikingly strong. If similar effects could be shown in humans, immune modulation by a few days of systemic corticosteroids, or more specific compounds, could open new approaches to rehabilitation after tendon injury.

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Section: Discussionmentioning

confidence: 99%

Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome

et al. 2018

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“…Some studies have found that the rate of fracture nonunion in HIV patients is significantly higher than that in normal people [46,47]. Jiang et al [48] reported that the proportion of Treg cells in patients with a nonunion fracture was significantly lower than that in patients with a normal union fracture. Further studies have shown that the Treg cell secretory function was significantly decreased in patients with nonunion fractures.…”

mentioning

confidence: 99%

The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6

Zheng

Wang

2020

BioMed Research International

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The aim of this study was to explore the effect of adenosine A2A receptor agonists on fracture healing and the regulation of the immunity system after bone fracture. We implanted fibrin gel containing adenosine A2A receptor agonist CGS 21680/inhibitor ZM 241385/saline locally in rat tibial fracture models, finding that the adenosine A2A receptor agonist could promote fracture healing. At the same time, the adenosine A2A receptor agonist decreased the level of IL-6 in blood and the fracture area, increased Treg cells, and decreased Th17 cells in blood of bone fracture rats. Further, tibial fracture rats implanted with the adenosine A2A receptor agonist gel were injected with IL-6. We found that IL-6 could reverse the effect of adenosine A2A receptor agonists on fracture healing and Treg/Th17 cells in blood. Through the above results, we believe that the adenosine A2A receptor agonist can promote fracture healing and regulate Treg/Th17 cells in blood of rats with fractures. These effects are related to IL-6.

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“…Hence, bone-resorbing osteoclast formation may be favored in these patients, suggesting a possible mechanism for delayed bone healing[ 182 ]. Another study supported the findings that multiple reductions in Tregs function in delayed healing patients could produce long-lasting consequences in the bone fracture healing process[ 183 ].…”

Section: Role Of the Adaptive Immune Response In Fracture Healingmentioning

confidence: 54%

Effects of immune cells on mesenchymal stem cells during fracture healing

Ehnert¹,

Relja²,

Schmidt‐Bleek³

et al. 2021

WJSC

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In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.

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Downregulation of regulatory T cell function in patients with delayed fracture healing

Cited by 14 publications

References 21 publications

Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome

Stimulation of Tendon Healing With Delayed Dexamethasone Treatment Is Modified by the Microbiome

The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6

Effects of immune cells on mesenchymal stem cells during fracture healing

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