Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage

Abstract

Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.

The Interplay Between Neutrophils and CD8+ T Cells Improves Survival in Human Colorectal Cancer

“…In particular, cell-cell interactions mediated by OX40, CD58, CD59, and their ligands have been proposed (12,31). Alternatively, a role for ROS release has also been suggested (42). Our data suggest that CD11a/CD54 interaction powerfully contributes to the elicitation of the costimulatory effects of neutrophils on CD8þ T-cell activation.…”

“…Neutrophil-CD8 þ Tcell interactions might indeed be operational in a wider range of conditions, thus supporting the notion of a highly effective cooperation between innate and adaptive immune responses. Remarkably, similar results have also emerged from studies conducted in experimental models (42) and in clinical settings, including early-stage lung cancer (12,13) and autoimmune and infectious disease (31). Underlying molecular mechanisms have not been fully clarified.…”

Mechanistic Understanding of Contact Allergy

“…It remains to be shown how mast cells and neutrophils are activated by contact allergens. Also, PRRs may play a role here as recently demonstrated for TLR-dependent neutrophil activation in graft-versus-host disease [25]. Interestingly, a recent study revealed that neutrophils leave chemokine cues for T cell migration in the airways.…”

Diabetes Mellitus: Role of Free Radicals and Oxidative Stress

“…) and peroxynitrite were also interact with ROS, and all of these species were known as RONS which is produced by immune system [57] but excessive production of RONS would damaged almost all classes of biomolecules, such as lipids [58] proteins [59] and DNA. [60,61] The term "oxidative stress" was introduced in 1970s and 1980s to describe these deleterious processes.…”