Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT.

Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease

“…While neutrophils have a well-known role in host defense against pathogens, recent studies have described various effector functions of neutrophils. 33 Although the role of neutrophils in the pathology of GVHD is not fully understood, production of reactive oxygen species and antigen presentation by neutrophils affected the severity of intestinal acute GVHD. 34,35 Moreover, release of NETs caused epitheliopathy and delayed epithelial wound healing in ocular chronic GVHD.…”

“…Among them, IL‐26 appeared to be involved in the marked increase in neutrophil levels (Figures 1C and 2B). While neutrophils have a well‐known role in host defense against pathogens, recent studies have described various effector functions of neutrophils 33 . Although the role of neutrophils in the pathology of GVHD is not fully understood, production of reactive oxygen species and antigen presentation by neutrophils affected the severity of intestinal acute GVHD 34,35 .…”

A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD

“…Intestinal bacteria, MAMPs (microorganism-related molecular patterns), and PAMPs are translocated to the lamina propria, which are recognized by Toll-like receptors and presented to T cells by DCs, activating effector T cells, further aggravating the intestinal mucosal injury [ 84 ]. At the same time, the infiltration of neutrophils into the small intestine promotes the development of GI GVHD through the production of reactive oxygen species, resulting in increased tissue damage [ 85 ]. In addition, GVHD can also attack B cells, goblet cells, Paneth cells, and mucous layers at the bottom of the crypts and aggravate intestinal inflammation and bacterial translocation, greatly increasing the susceptibility of the recipient to infection [ 13 , 84 ] ( Figure 1 ).…”

Neutrophils as regulators of macrophage-induced inflammation in a setting of allogeneic bone marrow transplantation

“…Recently, neutrophils have been found to play regulatory roles in both innate and adaptive immune responses ( Reber et al., 2017 ; Marwick et al., 2018 ; Germann et al., 2020 ). As they are the most rapidly reconstituted innate immune cells after HSCT, the number of circulating neutrophils in HSCT patients has long been used as an indicator for effective engraftment of donor cells in recipient marrows ( Storek, 2008 ; Tecchio and Cassatella, 2021 ). Although neutrophils perform multifaceted functions in inflammation, studies of neutrophil functions and their roles during sepsis post-HSCT are still lacking.…”