Early systemic immune biomarkers predict bone regeneration after trauma

Abstract

Severe traumatic injuries are a widespread and challenging clinical problem, and yet the factors that drive successful healing and restoration of function are still not well understood. One recently identified risk factor for poor healing outcomes is a dysregulated immune response following injury. In a preclinical model of orthopedic trauma, we demonstrate that distinct systemic immune profiles are correlated with impaired bone regeneration. Most notably, elevated blood levels of myeloid-derived suppressor cells (MDSCs) and the immunosuppressive cytokine interleukin-10 (IL-10) are negatively correlated with functional bone regeneration as early as 1 wk posttreatment. Nonlinear multivariate regression also implicated these two factors as the most influential in predictive computational models. These results support a significant relationship between early systemic immune responses to trauma and subsequent local bone regeneration and indicate that elevated circulating levels of MDSCs and IL-10 may be predictive of poor functional healing outcomes and represent novel targets for immunotherapeutic intervention.

An atlas of dynamic peripheral blood mononuclear cell landscapes in human perioperative anaesthesia/surgery

“…Surgical trauma can affect the dynamic changes occurring in PBMCs during the perioperative period. Specifically, surgical trauma activates various stress responses, causing the release of catecholamines, cortisol and inflammatory mediators, 22 which further strengthens the perioperative inflammatory response and immune suppression, 23 , 24 and even leads to immune cell dysfunction, thus triggering changes in PBMCs. 25 Effector B cells may have been the cluster the most affected by surgical trauma in the present study.…”

Review of immunological plasma markers for longitudinal analysis of inflammation and infection in rat models

“…Injury induces an immunological response from acute tissue damage incurred during surgical procedures such as laparotomy, 31 castration, 23 or implantation of a biomaterial. Additionally, inflammation can be induced via bone fracture 40 or creation of segmental bone defects 2 …”

“…An additional model involved testing a panel of cells, cytokines, and chemokines to understand the immune response during bone healing in 13‐week‐old Sprague Dawley rats with critically sized (8 mm) femoral defects 2 . Through multivariate analysis of responses in rats receiving either immediate or delayed (at 8 weeks) treatment with bone morphogenetic protein‐2 in alginate hydrogel and a polycaprolactone (PCL) mesh, Cheng et al 2 found B cells, IL‐6, IL‐13, and IL‐1α correlated with successful healing. Additionally, IFN‐γ induced protein‐10 (IP‐10), myeloid‐derived suppressor cells (MDSCs), and cytotoxic T cells were indicative of poor healing.…”

“…Following injury or infection, an inflammatory response is initiated, as the body attempts to resolve or contain the injurious stimulus. Initially, proinflammatory cytokines, such as interleukin (IL)−1, IL‐6, and tumor necrosis factor‐α (TNF‐α), are produced 1,2 . As these cytokines rise in concentration, they signal production of anti‐inflammatory cytokines such as interleukin‐1 receptor antagonist (IL‐1RA), IL‐10, and transforming growth factor‐β (TGF‐β) 1 .…”

“…Chronic inflammation is characterized by tissue destruction and/or sustained levels of acute phase proteins (APPs) 3–5 . In contrast, acute inflammation begins to resolve after 24–48 h with rising anti‐inflammatory protein concentrations to halt production of APPs 2,3 …”