Neutrophils as regulators of the hematopoietic niche

Abstract

The niche that supports hematopoietic stem and progenitor cells (HSPCs) in the bone marrow is a highly dynamic structure. It maintains core properties of HSPCs in the steady state, and modulates their proliferation and differentiation in response to changing physiological demands or pathological insults. The dynamic and environment-sensing properties of the niche are shared by the innate immune system. Thus, it is not surprising that innate immune cells, including macrophages and neutrophils, are now recognized as important regulators of the hematopoietic niche and, ultimately, of the stem cells from which they derive. This review synthesizes emerging concepts on niche regulation by immune cells, with a particular emphasis on neutrophils. We argue that the unique developmental, circadian, and migratory properties of neutrophils underlie their critical contributions as regulators of the hematopoietic niche.

Figure 1.

Functional and phenotypic diversity of neutrophils in the bone marrow. Neutrophils are produced inside of the bone marrow (BM) through progressive maturation of hematopoietic progenitors (long-term hematopoietic stem cells [LT-HSCs] to GMPs). Proliferative precursors (NeP and preNeu) differentiate into immature neutrophils and finally into mature neutrophils that are released into blood. A fraction of aged neutrophils return into the marrow after several hours in the circulation. Top and bottom panels indicate specific phenotypes and functions, respectively, of neutrophils at each stage of their life cycle. HSC, hematopoietic stem cell; HSCT, hematopoietic stem cell transplantation; HSPC, hematopoietic stem and progenitor cell; MPP, multipotent progenitor; ST, short-term; TNF, tumor necrosis factor. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 2.

Regulation of the hematopoietic bone marrow niche. The sympathetic nervous system (SNS) exerts control on the HSC niche by the circadian release of catecholamine, which targets β3-adrenergic receptors on stroma cells. The same signals can act through neutrophils to produce prostaglandin E2 (PGE₂) and stimulate the osteoblastic niche. The stromal niche is also circadianally regulated by aged neutrophils that return to the bone marrow after only several hours in the circulation. Aged neutrophils that infiltrate the bone marrow are engulfed by macrophages and activation of the LXRs lead to inhibition of the hematopoietic niche. Excessive G-CSF production associated with several inflammatory processes or impaired neutrophil clearance in extramedullary tissues is also a potent inhibitor of the HSPC niche. All of these regulatory mechanisms ultimately inhibit production of CXCL12, thereby promoting HSPC egress into blood. This has been shown in the intestine, where neutrophil infiltration in the mucosa and engulfment of neutrophils by tissue-resident macrophages inhibits the IL-23/IL-17/G-CSF axis and remotely supports niche activity in a circadian-independent manner. Boxes indicate the presence or absence of circadian oscillations in each tissue. Professional illustration by Patrick Lane, ScEYEnce Studios.