Neutrophils in acute inflammation: current concepts and translational implications

Abstract

Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while, at the same time, limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, 1 of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include capturing, rolling, adhesion, crawling, and transmigration, as well as a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. The use of therapeutics modulating neutrophil activation responses, as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades, have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.

Graphical abstract

Figure 1

Updated leukocyte recruitment cascade and translational implications. Free-flowing neutrophils are captured by transient PSGL-1–selectin and VLA-4–VCAM/VLA-6–laminin interactions. Rolling (fast: P-selectin; slow: E-selectin) is impacted by PSGL-1 and ESL-1 binding to their selectin partners, as well as CD44, which, in a lipid raft and Bruton tyrosine kinase (BTK)-dependent manner, affects E-selectin–mediated slow rolling. Chemokine-mediated full activation of LFA-1 leads to ICAM-1–dependent firm neutrophil adhesion. This adhesive bond is further strengthened by Mac-1 interactions. Signaling elements and recruitment cues involved in integrin activation include talin-1 and kindlin-3. The subsequent slower crawling toward endothelial access points is primarily controlled by CXCL-1, whereas the transmigration toward the abluminal side is CXCL 2 dependent, followed by another step of abluminal CXCL-1–dependent crawling. Neutrophil transmigration depends on pore size selection and is additionally facilitated by mast cell–derived tumor necrosis factor (TNF). Neutrophils exert their functions within the tissue but are capable of reentering the blood circulation (reverse transmigration) in a Mac-1, neutrophil elastase, LTB-4, JAM-C–dependent pathway, taking on an activated phenotype. Different translational studies and observations have been performed to highlight implications of distinct mechanistic cues in neutrophil recruitment and functionality (upper letters). mAb, monoclonal antibody; MMPs, matrix metalloproteinase; NE, neutrophil elastase; PEU, perivascular extravasation unit; 3D, three dimensional.

Figure 2

Regulators of neutrophil trafficking. (A) Integrin activation is distinctly regulated. Selectin engagement results in the intermediate conformation of the integrin, which requires talin-1 binding to the integrin cytoplasmic tail. The high-affinity conformation requires the presence of talin-1 and kindlin-3. Talin-1 binding relies on formation of a complex with Rap1 and RIAM, whereas kindlin-3 is recruited to the integrin prior to induction of the high-affinity conformation and transmits its activation signal toward LFA-1 in an ILK, PKC, and pH-domain–dependent manner. Mechanistic differences between LFA-1 and Mac-1 exist in that Mac-1 activation depends on ArhGAP15 and Bruton tyrosine kinase (BTK). LRP1 can bind via the I domain to Mac-1 and to a lesser extent to LFA-1. (B) Reverse-transmigrated neutrophils can recirculate and impact leakage even at remote organs, such as the lung. The lung-resident marginated pool of neutrophils undergoes fast Abl kinase–dependent phenotypic changes upon LPS challenge to prime the cells for bacterial “hunting.” Overall, neutrophils exert effects within different tissues but are equally impacted and modulated by their surroundings. (C) Circadian rhythms dictate leukocyte release, function and clearance, impacting and modulating many subsequent activation and recruitment mechanisms. (D) Neutrophils interact with endothelial cells, which mediates recruitment and activation. Interaction with platelets helps in activation, priming, and recruitment to inflamed or injured tissue but also occurs during thrombus formation. Interaction of neutrophils with regulatory T cells (Treg) evokes interleukin-10 (IL-10) release by neutrophils. Neutrophil-erythrocyte interaction is prominent in sickle cell disease. Additionally, erythrocytes contain a variety of cytokines that can impact neutrophil functionality.

Figure 3

Translational considerations. (A) An adequate assessment of neutrophils present, the degree and necessity of inflammatory reactions, and evaluation of possible therapeutics must be performed. (B) Leukocyte dysfunction is observable in genetic diseases. Leukocyte adhesion deficiencies result in an increased risk for infections due to different underlying causes. Also, other causes affecting neutrophils are known, including transfusion, extracorporeal circulation, and inflammatory diseases. Patients require isolation and immunoprotective measures or adequate control of neutrophil hyperactivation and organ-protection strategies. (C) COVID-19–based considerations must take neutrophil phenotypes into account. Anti-inflammatory strategies are being discussed, but more precise interventions are needed. Distinguishing between the acute and long phases of COVID are important. Targeted approaches seem to be promising for future endeavors in the therapy of COVID, sepsis, or acute respiratory distress syndrome. (D) Consideration of circadian rhythmicity is crucial for future therapeutic endeavors. Rescheduling of surgeries or interventions is needed, and chronotherapy, light therapy, and sleep interventions are in place. CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; IgE, immunoglobulin E; WAS, Wiskott-Aldrich syndrome.

Figure 4

Common clinical findings. Common findings can include changes in neutrophil numbers (neutrophilia vs neutropenia), deranged circadian rhythms, or patients with various medications scheduled for surgery or other medical interventions. Causality is to be assessed, and advanced diagnostics or interventions should be planned in a timely manner prior to/in parallel with subsequent treatments. BTK, Bruton tyrosine kinase; ROS, reactive oxygen species; !, current situation; ?, possible cause/s; >, consequences.