Mechanisms regulating neutrophil responses in immunity, allergy, and autoimmunity

Abstract

Neutrophil granulocytes, or neutrophils, are the most abundant circulating leukocytes in humans and indispensable for antimicrobial immunity, as exemplified in patients with inborn and acquired defects of neutrophils. Neutrophils were long regarded as the foot soldiers of the immune system, solely destined to execute a set of effector functions against invading pathogens before undergoing apoptosis, the latter of which was ascribed to their short life span. This simplistic understanding of neutrophils has now been revised on the basis of insights gained from the use of mouse models and single-cell high-throughput techniques, revealing tissue- and context-specific roles of neutrophils in guiding immune responses. These studies also demonstrated that neutrophil responses were controlled by sophisticated feedback mechanisms, including directed chemotaxis of neutrophils to tissue-draining lymph nodes resulting in modulation of antimicrobial immunity and inflammation. Moreover, findings in mice and humans showed that neutrophil responses adapted to different deterministic cytokine signals, which controlled their migration and effector function as well as, notably, their biologic clock by affecting the kinetics of their aging. These mechanistic insights have important implications for health and disease in humans, particularly, in allergic diseases, such as atopic dermatitis and allergic asthma bronchiale, as well as in autoinflammatory and autoimmune diseases. Hence, our improved understanding of neutrophils sheds light on novel therapeutic avenues, focusing on molecularly defined biologic agents.

Keywords: autoimmunity; autoinflammation; immunodeficiency; infection; inflammation.

FIGURE 1

Summary of different neutrophil functions. (A) Effective migration is a prerequisite to any subsequent function executed by neutrophils. Neutrophils in circulation rely on various interactions with the endothelium. These include (1) loose binding of carbohydrate ligands on neutrophils (such as sialyl‐Lewis^X and P‐selectin glycoprotein ligand 1) to selectins (E‐selectin and P‐selectin, respectively) on activated endothelium, which induce rolling of neutrophils along endothelial cells; (2) sensing of chemokines (including CXCL8) by chemokine receptors on neutrophils (e.g., CXCR2), which in turn activates the integrins lymphocyte function‐associated antigen 1 (LFA‐1, consisting of CD11a and CD18) and complement receptor 3 (CR3; made of CD11b and CD18) on neutrophils; (3) the activated integrins LFA‐1 and CR3 on neutrophils strongly adhere to intercellular adhesion molecule 1 (ICAM‐1) and ICAM‐2 on activated endothelial cells, thus arresting neutrophils and allowing their transmigration through the endothelium (also called extravasation) into the tissue. Neutrophil migration, facilitated by adhesion molecules and chemotactic sensors for recruitment, is absolutely crucial, as illustrated by immunodeficiencies due to leukocyte adhesion deficiency (please see Table 1) that can lead to life‐threatening conditions. (B) Neutrophils are excellent at direct combat and feature a wide repertoire of effector functions, such as phagocytosis, degranulation of primary, secondary, tertiary, and secretory vesicles, production of reactive oxygen species (ROS; such as superoxide [O₂ ⁻], hydrogen peroxide [H₂O₂], and hypochloride [HOCl]), and release of neutrophil extracellular traps (NETs) consisting of either nuclear or mitochondrial DNA. (C) Their rapid mobilization to affected tissues allows neutrophils to guide the recruitment and activity of other cells involved in the inflammatory process, such as dendritic cells (DCs), monocytes (Mono), macrophages (Macs), CD4⁺ T helper cells, and CD8⁺ cytotoxic T cells by releasing or leaving “trails” of chemokines (such as CXCL12 and CCL3) and cytokines (e.g., epidermal growth factor [EGF]). (D) Whereas the importance of neutrophils for immune defense is irrefutable, recent evidence suggests they are also involved in tissue‐specific non‐immune processes. Neutrophils extravasate to various tissues at steady state and engage in non‐canonical functions, such as angiogenesis, tissue repair, and wound healing.

FIGURE 2

Neutrophil clearance regulates tissue inflammation. Upon infection, increased levels of granulocyte colony‐stimulating factor (G‐CSF) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) induce granulopoiesis and promote neutrophil release from the bone marrow. C‐X‐C motif chemokine receptor 2 (CXCR2)^high neutrophils leave the bone marrow and migrate toward affected tissues, following gradients of intermediate and end‐target chemoattractants. Recognition of pathogen‐associated molecular patterns (PAMPs) in the tissue upregulates CC motif chemokine receptor 7 (CCR7) on neutrophils, allowing them to migrate via afferent lymphatics into draining lymph nodes (dLNs) where apoptosis‐prone neutrophils coming from the tissue are phagocytosed by dLN‐resident conventional DCs (cDCs). Neutrophil phagocytosis impedes interleukin (IL)‐23 production by cDCs, in turn leading to reduced synthesis of G‐CSF. Thus, CCR7‐dependent tissue neutrophil clearance provides a negative feedback loop for neutrophil immune responses and limits tissue damage.

FIGURE 3

IL‐4R signaling accelerates neutrophil aging. Circulating fresh neutrophils in healthy individuals can perform a variety of effector functions, including neutrophil extracellular trap (NET) release, reactive oxygen species (ROS) production, degranulation, and phagocytosis. An increase in the type 2 immune cytokines interleukin (IL)‐4 and IL‐13 affects phenotypical and functional properties of neutrophils and accelerates their aging. Aged neutrophils lose their granularity as well as ability to perform chemotaxis, phagocytosis, and NET release, whereas they are more prone to ROS production. The functional alterations are evident in type 2 immune diseases with increased IL‐4 and IL‐13 abundance. In mild‐to‐moderate disease manifestations, neutrophil counts are reduced in the affected tissues, but are found at normal levels in the blood. In severe type 2 immune skewing (e.g., by very high systemic concentrations of IL‐4), neutrophil counts can be reduced in blood and tissues.

FIGURE 4

Neutrophils contribute to pathology of autoinflammatory and autoimmune diseases. A key driver of autoinflammation is IL‐1β, a cytokine that potently stimulates neutrophil survival and activity. Neutrophils can also contribute to the production of IL‐1β, thus creating an inflammatory positive feedback loop. Increased IL‐1β signaling prompts activated neutrophils to perpetuate autoinflammation through effector functions and cytokine release. In autoimmunity, neutrophils enhance activation of self‐reactive adaptive immune cells, especially T helper 17 (Th17) cells driving type 3 immune diseases. Thus, immune complexes exposed upon NET formation can stimulate plasmacytoid dendritic cells (pDCs) via endosomal Toll‐like receptors (TLRs) to produce type I interferons (IFN‐I). This, in turn, leads to IL‐23 release by conventional DCs (cDCs) and subsequent priming of Th17 cells. Neutrophils can also facilitate autoantibody production since they release various autoantigens upon activation, through degranulation, ROS production, and NET release. Both Th17 cells and autoantibodies can further activate neutrophils and cause tissue pathology.