Mechanisms and Therapeutic Modulation of Neutrophil-Mediated Inflammation

Abstract

Neutrophils are abundant, short-lived myeloid cells that are readily recruitable to sites of inflammation, where they serve as first-line defense against infection and other types of insult to the host. In recent years, there has been increased understanding on the involvement of neutrophils in chronic inflammatory diseases, where they may act as direct effectors of destructive inflammation. However, destructive tissue inflammation is also instigated in settings of neutrophil paucity, suggesting that neutrophils also mediate critical homeostatic functions. The activity of neutrophils is regulated by a variety of local tissue factors. In addition, systemic metabolic conditions, such as hypercholesterolemia and hyperglycemia, affect the production and mobilization of neutrophils from the bone marrow. Moreover, according to the recently emerged concept of innate immune memory, the functions of neutrophils can be enhanced through the process of trained granulopoiesis. This process may have both beneficial and potentially destructive effects, depending on context, that is, protective against infections and tumors, while destructive in the context of chronic inflammatory conditions. Although we are far from a complete understanding of the mechanisms underlying the regulation and function of neutrophils, current insights enable the development of targeted therapeutic interventions that can restrain neutrophil-mediated inflammation in chronic inflammatory diseases, such as periodontitis.

Keywords: complement; host modulation; metabolic dysregulation; myeloid cells; periodontitis; trained immunity.

Figure 1.

Mobilization, recruitment, and functions of neutrophils in infected/inflamed tissue. The granulocyte colony-stimulating factor (G-CSF) plays a key role in promoting neutrophil mobilization and release from the bone marrow, while antagonizing the neutrophil-retentive interaction between the CXC-chemokine receptor 4 (CXCR4) and CXC-chemokine ligand 12 (CXCL12) (Manz and Boettcher 2014). After their release into the blood circulation, the neutrophils can be recruited to peripheral tissues in response to infection and/or inflammation. In this process, the circulating neutrophils undergo a series of tightly regulated rolling, adhesive, and crawling interactions with the endothelium followed by their extravasation (or diapedesis) into the tissue (Ley et al. 2018). Once in the tissue, neutrophils migrate in response to chemotactic gradients of host-derived chemokines and inflammatory mediators and/or pathogen-derived molecules, and they perform a variety of defensive functions, as indicated (Burn et al. 2021). The clearance via efferocytosis of dying (apoptotic) neutrophils by tissue macrophages is crucial for the resolution of inflammation (Hajishengallis and Chavakis 2019). NET, neutrophil extracellular trap.

Figure 2.

The IL-23→IL-17→G-CSF axis and its regulation. The IL-23–IL-17–G-CSF cytokine cascade and cellular sources of the cytokines involved (left panel). Apoptotic neutrophils are cleared by efferocytosis by tissue macrophages, leading to suppression of IL-23 production in the latter, in turn, downregulating the production of IL-17 and hence of G-CSF (right panel). The proper function of the IL-23→IL-17→G-CSF axis helps maintain steady-state neutrophil counts (Ley et al. 2018). Dashed arrows indicate reduced activation and production. IL, interleukin; G-CSF, granulocyte colony-stimulating factor.

Figure 3.

Trained granulopoiesis. Trained innate immunity, a form of epigenetic immune/inflammatory memory, can be induced in the bone marrow by certain inflammatory and microbial stimuli, such as the fungally derived β-glucan (Mitroulis et al. 2018; Netea et al. 2020). Trained hematopoietic stem and progenitor cells display myeloid-biased differentiation and give rise to increased numbers of neutrophils with enhanced immune and inflammatory responsiveness (“trained granulopoiesis”) (Mitroulis et al. 2018; Chavakis et al. 2019). Epigenetic adaptations in granulocyte-monocyte progenitors (GMPs) are transmitted to neutrophils, which exhibit enhanced capacity to kill tumors (Kalafati et al. 2020). Trained myeloid cells, including neutrophils, also display enhanced antimicrobial activities and contribute to protection from future infections (Netea et al. 2020). However, the enhanced immune responsiveness of trained neutrophils is also thought to contribute to increased inflammatory tissue damage in the setting of inflammatory diseases, such as atherosclerosis and periodontitis (Hajishengallis and Chavakis 2021). HSC, hematopoietic stem cell; MPP, multipotent progenitor.

Figure 4.

Therapeutic modulation of neutrophil-mediated inflammation. Targeted therapeutic interventions that can potentially restrain the initiation and persistence of neutrophil-mediated tissue inflammation by suppressing the recruitment (A) or the activation (B) of neutrophils as well as their ability to release neutrophil extracellular traps (NETs) (C). In addition, or alternatively, approaches to enhance the apoptosis and/or the efferocytosis of neutrophils by macrophages can promote inflammation resolution (D). See text for details. BLT1, leukotriene B4 receptor 1; CDK9, cyclin-dependent kinase 9; DEL-1, developmental endothelial locus 1; FPR1, formyl-peptide receptor 1; GDF-15, growth differentiation factor 15; ICAM-1, intercellular adhesion molecule 1; LXR, liver X receptor; MPO, myeloperoxidase; PAD-4, protein-arginine deiminase type 4.