Date Published: May 2, 2019
Publisher: Public Library of Science
Author(s): Tomohiro Kawano, Munehisa Shimamura, Hironori Nakagami, Hideaki Kanki, Tsutomu Sasaki, Hideki Mochizuki, Masaki Mogi.
Although T cells play important roles in the pathophysiology of ischemic stroke, the dynamics of T cells remains unclear. In cancer, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) contribute to the maintenance of the tumor microenvironment by suppressing T cells. However, the presence of these cells has never been examined in ischemic brain. Therefore, we examined the temporal and spatial profiles of PMN-MDSCs, which are defined as the CD11b+Ly6ClowLy6G+ cells with higher expression levels of Nox2 and C/EBP Homologous Protein (CHOP) mRNA than normal neutrophil. Fluorescence-activated cell sorter (FACS) analysis showed that the count of CD11b+Ly6ClowLy6G+ cells was increased in the ischemic hemisphere and bone marrow at 72 hours, as well as in the spleen 24 hours after transient middle cerebral artery occlusion in mice. In contrast, the contralateral hemisphere, normal bone marrow, and normal spleen contained few CD11b+Ly6ClowLy6G+ cells. Real-time reverse transcription polymerase chain reaction revealed that CD11b+Ly6ClowLy6G+ cells sorted from brain and spleen 72 hours after ischemia had greater expression of Nox2 and CHOP mRNA than neutrophils in bone marrow, suggesting that these cells constitute PMN-MDSCs. Immunohistochemistry showed that CD11b+Ly6G+ cells were located in the ischemic core and border zone, indicating that PMN-MDSCs might be endemic to these regions. Although neutrophils are believed to invade infarct regions 48–72 hours after ischemia, the present study suggested that some of these cells are in fact PMN-MDSCs. Further studies on the function of PMN-MDSCs might unveil the unknown mechanisms of T cell activation and recruitment in ischemic stroke.
Inflammation and immune cells play important roles in the pathology of ischemic stroke. Following brain ischemia, microglia are activated by damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and high-mobility group box 1, which are released from injured cells . Activated microglia release several proinflammatory cytokines, such as interleukin 1-beta (IL-1β), IL-6, and tumor necrosis factor (TNF), which prime dendritic cells for antigen presentation. Activated dendritic cells then facilitate T cell responses .
In the present study, we demonstrated that CD11b+Ly6ClowLy6G+ cells with high expression of Nox2 and CHOP mRNA were present in the brain and spleen after ischemic stroke. Because the expression pattern of Nox2 and CHOP mRNA is different in neutrophils, these cells must be PMN-MDSC-LCs.