Regulatory B cell is critical in bone union process through suppressing proinflammatory cytokines and stimulating Foxp3 in Treg cells

Abstract

Bone fractures may result in delayed union (DU) or non-union (NU) in some patients. Evidence suggests that the skewing of the immune system toward the proinflammatory type is a contributing factor. Because B cells were previously found to infiltrate the fracture healing site at abundant levels, we examined the regulatory B cells (Bregs) in DU/NU patients. In bone fracture patients with normal healing, the frequency of interleukin (IL)-10-expressing B cells was significantly upregulated in the early healing process (6 weeks post-surgery) and was downregulated later on (18 weeks post-surgery), whereas in DU/NU patients, the early upregulation of IL-10-expressing B cells was missing. The majority of IL-10-expressing B cells were concentrated in the IgM CD27 fraction in both controls and patients. IgM CD27 B cells effectively suppressed interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-2 expression from CD4 T cells, as well as IFN-γ and TNF-α expression from CD8 T cells. The IgM CD27 B cell-mediated suppression was restricted to the sample from the early healing time point in controls, as the IgM CD27 B cells from normal healing patients later on or from DU/NU patients did not present significant regulatory function. In addition, culturing of CD4 CD25 Tregs with IgM CD27 B cells from controls at early healing time point resulted in higher Foxp3 expression, a function absent in controls at later time point, or in DU/NU patients. In conclusion, our results support a role of B cell-mediated regulation early during the bone healing process.

Regulatory B cells induced by ultraviolet B through toll‐like receptor 4 signalling contribute to the suppression of contact hypersensitivity responses in mice

“…Sun et al. reported that regulatory B cells were critical in the bone union process by stimulating regulatory T cells . Song et al.…”

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

“…Also, IL6 knockout mice have delayed callus mineralization and maturation (Wallace, Cooney, Englund, & Lubahn, ; Yang et al., ), but mice that lack the IL1 receptor do not show considerable changes (Lange et al., ). Even though IL10 or other anti‐inflammatory cytokines are abundantly present in the fracture haematoma, their role during fracture healing remains unclear (Hauser et al., ; Sun et al., ).…”

Fracture Repair: Its Pathomechanism and Disturbances

“…This mechanism seems to depend on regulatory B and T lymphocytes (B regs and T regs ), as they were shown to participate in fracture healing. B regs were presented to suppress the inflammatory phase secreting antiinflammatory cytokines IL-10 (interleukin-10) and TGF-β (transforming growth factor-β), and enhancing maturation of T regs [15]. At the early phase of the reparative processes, they probably prevent from auto aggression against infiltrating progenitors, thus enabling them to proliferate and differentiate into bone forming cells.…”