title: Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a major health and socioeconomic problem as it is associated with high rates of mortality and morbidity worldwide. Regulatory T cells (Tregs) have been reported to reduce inflammatory response in several diseases, including myasthenia gravis, viral myocarditis and cerebral infarction. The present study investigated the role of Tregs in mediating neuro‑protective effects in a mouse model of TBI. Initially, Treg levels were determined, and compared between the controlled cortical impact (CCI) model for moderate TBI and the sham group, by using flow cytometry and ELISA. Afterwards, the number of Tregs was upregulated (by injection) and downregulated (by depletion), respectively, to elucidate the effect of Tregs in the presence of an inflammatory reaction and a deficient neurological function and consequently, in the prognosis of TBI in the mouse. The expression of pro‑inflammatory cytokines [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6)] and anti‑inflammatory cytokines [IL‑10, transforming growth factor (TGF)‑β] in blood and brain tissues was also measured in the five groups: Μice receiving a saline injection, mice experiencing Treg depletion, small‑dose (SD Tregs, 1.25x105), and mice receiving different doses of Tregs: Moderate‑dose (MD Tregs, 2.5x105) and large‑dose (LD Tregs, 5x105), using ELISA and PCR. Co‑cultures of Tregs and microglia were performed to evaluate the expression of pro‑inflammatory cytokines and observe the interaction between the two types of cells. The regulation patterns in JNK‑NF‑κB pathway by Tregs were also evaluated by western blot analysis. Treg levels were significantly reduced in TBI mouse group on the 3rd day after TBI (P<0.05). In the mouse model of TBI, the expression of pro‑inflammatory cytokines (TNF‑α, IL‑1β, IL‑6) was enhanced, while the expression of anti‑inflammatory cytokines (IL‑10, TGF‑β) was reduced (P<0.05). Tregs exhibited a suppressive effect on inflammatory reactions. In the MD group, the activation of microglia cells was markedly inhibited, compared to the activation in SD and LD groups. The expression of ERK1/2, JNK1/2/3 and NK‑κB was significantly downregulated in the MD group. The results indicated that Tregs exhibited significant neuro‑protective effects, suppressing pro‑inflammatory responses and promoting tissue repair after TBI injury in the mouse, specifically by deactivating the JNK‑NF‑κB pathway. The results of the study show that Tregs potentially participates in neuro‑therapeutic approaches for TBI.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yunhu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Cerebrovascular Disease, The First Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Cao
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China.
authors.forename: Qishan
authors.initials: Q
authors.lastname: Ran
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D015415:Biomarkers; D000070642:Brain Injuries, Traumatic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D020935:MAP Kinase Signaling System; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines