Systemic administration of all-trans retinoic acid modulated circulating immune cells but failed to improve healing in a preclinical model of musculoskeletal trauma.

Musculoskeletal trauma is exceedingly common and experiences a high incidence of complications, including bone non-union. Previous studies have implicated a dysregulated systemic immune response after injury as an important factor contributing to complications. We have previously identified a negative correlation between circulating myeloid-derived suppressor cells (MDSCs) and bone regeneration in a rat model of composite bone and muscle trauma. MDSCs are an immature, heterogeneous cell population of myeloid lineage that expands after injury and possesses potent immunosuppressive functions including the inhibition of T cells and expansion of regulatory T cells (Tregs), which could contribute to poor outcomes. As such, they may represent a novel therapeutic target in bone trauma. All-trans retinoic acid (ATRA) is a vitamin A derivative that has previously been shown to reduce MDSCs in cancer models by promoting their differentiation into mature myeloid cell populations. However, ATRA's effects on MDSCs have not been explored in the context of trauma. Here, we investigated the effects of ATRA on peripheral blood immune cells both in vitro and in vivo using a rodent model of bone and muscle trauma. Treatment with ATRA depleted MDSCs in blood derived from traumatized rats in vitro. Further, in vivo studies revealed that a specific subset of MDSCs were depleted by systemic ATRA administration. Tregs were also depleted and correlated negatively with endpoint bone healing, although healing overall was not altered by ATRA treatment. Additionally, higher doses of ATRA had the unanticipated effect of increasing rather than decreasing circulating MDSC levels. Further studies will be necessary to develop and optimize immunomodulatory interventions targeting systemic immune dysregulation after trauma and to determine whether such interventions possess the potential to improve functional bone regenerative outcomes.