Neutrophil granulocytes enhance graft-versus-host disease via tissue damage

Neutrophils are the largest human white blood cell population, T cells are the main cause of tissue damage in GVHD, here we want to identify the events leading up to T cell recruitment and activation.

To explore the role for neutrophils in GVHD-related mortality, we used an anti-Ly6G antibody–based depletion approach. Treatment with Anti-Ly6G antibody reduced the numbers of circulating neutrophils without affecting the numbers of monocytes or macrophages. By in vivo myeloperoxidase imaging, we tested the neutrophil penetration of the mouse ileum after allo-HCT and found that myeloperoxidase-positive cells accumulate following allo-HCT in the terminal ileum.

Next, we test whether physical or genetic depletion of neutrophils can reduce GVHD-related mortality. The answer is yes. Besides, reactive oxygen species (ROS) plays an important role in this process. When knock down the ROS gene NOX2, we found that loss of NOX2 in neutrophils damaging ROS production led to lower levels of tissue damage, GVHD-related mortality.

Treated CD34+ cells were characterized based on the upregulation of pluripotency genes including SOX2, OCT4, NANOG, and zinc finger protein of the cerebellum family member 3. siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%.

The researchers conducted experiments involving laboratory cell cultures of human glioblastoma cells and glioblastoma tumors transplanted in mice. Compared with normal human and mouse tissue, the researchers found that AMPK was highly active in human and mouse glioblastoma cells. They then treated the cancer cells with metformin and conducted a series of genetic tests to determine the molecular pathways it uses to stop the cancer growth. Those tests showed clearly that metformin directly inhibited the mTOR pathway and the cancer by promoting the interaction of 2 upstream molecules that stop the pathway's function.

This work indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.

To evaluate the contribution of bacterial activation of neutrophils, we compared WT neutrophils to those who lacking TLR2, TLR3, TLR4, TLR7 and TLR9. When we transferred neutrophils lacking Toll-like receptors TLR2/3/4/7/9?, Gvhd severity was reduced. So the neutrophil-mediated tissue damage requires neutrophil activation via TLRs.

To summary, this work indicates a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.