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Review
. 2023 Mar;314(1):142-157.
doi: 10.1111/imr.13142. Epub 2022 Oct 3.

The role of neutrophils in trained immunity

Lydia Kalafati  1 , Aikaterini Hatzioannou  1 , George Hajishengallis  2 , Triantafyllos Chavakis  1
Affiliations
Review

The role of neutrophils in trained immunity

Lydia Kalafati et al. Immunol Rev. 2023 Mar.

Abstract

The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone marrow (BM) progenitors (central trained immunity) and their innate immune cell progeny, thereby triggering elevated responsiveness against secondary stimuli. BM progenitors can respond to microbial and sterile signals, thereby possibly acquiring trained immunity-mediated long-lasting alterations that may shape the fate and function of their progeny, for example, neutrophils. Neutrophils, the most abundant innate immune cell population, are produced in the BM from committed progenitor cells in a process designated granulopoiesis. Neutrophils are the first responders against infectious or inflammatory challenges and have versatile functions in immunity. Together with other innate immune cells, neutrophils are effectors of peripheral trained immunity. However, given the short lifetime of neutrophils, their ability to acquire immunological memory may lie in the central training of their BM progenitors resulting in generation of reprogrammed, that is, "trained", neutrophils. Although trained immunity may have beneficial effects in infection or cancer, it may also mediate detrimental outcomes in chronic inflammation. Here, we review the emerging research area of trained immunity with a particular emphasis on the role of neutrophils and granulopoiesis.

Keywords: bone marrow; cancer; emergency myelopoiesis; granulopoiesis; hematopoietic stem and progenitor cells; inflammation; innate immune memory; trained immunity.

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Conflict of interest statement

Conflict of Interest: The authors have no conflict to disclose.

Figures

Fig. 1:
Fig. 1:. Central and Peripheral Trained Immunity
Central trained immunity defines that the process of myelopoiesis is trained by epigenetic rewiring of HSPCs (HSCs and MPPs) as well as of GMPs, thereby giving rise to more mature myeloid cells (neutrophils and monocytes) and importantly to myeloid cells with higher inflammatory potential. Agonists, such as the β-glucan or the BCG vaccine may promote central trained immunity in a manner that involves signaling by factors, such as GM-CSF, IL-1β, type I or type II IFNs. Induction of trained immunity also involves the direct modulation of the inflammatory preparedness of mature myeloid cells in the bloodstream or peripheral organs (peripheral trained immunity). BCG, Baccillus Calmette-Guerin; HSC, hematopoietic stem cell; MPP, multipotent progenitor; GMP, granulocyte-macrophage progenitor.
Fig. 2:
Fig. 2:. Neutrophils in Protective and Maladaptive Trained Immunity
Trained innate immunity and particularly trained granulopoiesis may exert both beneficial and detrimental effects. Trained immunity leads to sustained reprogramming of granulopoiesis with generation of trained neutrophils that display more potent effector mechanisms such as degranulation, ROS production, phagocytosis, antigen presentation, release of cytokines and other immune mediators, and increased expression of adhesion molecules and activation markers. Trained neutrophils may provide protection from infections or tumor or enhance tissue damage in the context of cardiometabolic or inflammatory diseases. BCG, Baccillus Calmette-Guerin; CXCR-4, C-X-C chemokine receptor type 4; VLA-4, very late antigen-4, NETs, neutrophil extracellular traps; ICAM-1, intracellular adhesion molecule 1; TLR-4, toll-like receptor 4; MPO, myeloperoxidase; ROS, reactive oxygen species.
Fig. 3:
Fig. 3:. Maladaptive Training of Neutrophils in the BM Contributes to the Emergence of Inflammatory Comorbidities.
Systemic inflammation induces epigenetically based inflammatory memory in HSPCs in the BM. Inflammation-adapted (trained) progenitors give rise to elevated production of neutrophils (and myeloid cells in general) with enhanced immune responsiveness to subsequent infectious or inflammatory challenges. These trained or hyper-responsive neutrophils infiltrate peripheral tissues, such as the periodontium and the joints, and exacerbate inflammatory disorders, such as periodontitis and arthritis. Because both periodontitis-induced and arthritis-induced systemic inflammation leads to inflammatory memory in the BM and increased susceptibility to either disease, it is concluded that maladaptive innate immune training of BM hematopoietic progenitors links distinct inflammatory comorbidities. HSC, hematopoietic stem cell; MPP, multipotent progenitor; GMP, granulocyte-monocyte progenitor.
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