New insights into constitutive neutrophil death

Abstract

Neutrophils undergo rapid aging and death known as constitutive or spontaneous death. Constitutive neutrophil death (CND) contributes to neutrophil homeostasis and inflammation resolution. CND has long been considered to be apoptotic until our findings reveal that it was a heterogeneous combination of diverse death. Furthermore, dead neutrophils retain functional roles via multiple manners. This review provides an overview of current research on the mechanism and modulation of CND. More noteworthy, we also summarize the after-death events of neutrophils. The fate of neutrophils can be changed under pathological conditions, so the involvement of CND in diseases and CND-related therapeutic strategies are also addressed.

Fig. 1. Mechanisms of constitutive neutrophil apoptosis.

Neutrophils regulate their constitutive apoptosis through ROS generation (blue a-b), interaction network among Bcl-2 family proteins (taupe a-d), MOMP and mitochondrial proteins (cyan a-c), caspases cascade (green), LMP and proteases (jasmine a-d), immunometabolism (orange a-b), the HIF (lilac), and many other newly discovered intracellular signaling pathways (pink a-d). (By Figdraw: IOURRcd466). ROS reactive oxygen species, ATMK ataxia-telangiectasia mutated kinase, NO nitric oxide, H4K16ac histone H4 acetylation at lysine 16, Bim Bcl-2-interacting mediator of cell death, Noxa phorbol-12-myristate-13-acetateinduced protein 1, Puma Bcl-2-binding component 3, Mcl-1 myeloid leukemia cell differentiation protein Mcl-1, Bak Bcl-2 homologous antagonist/killer, Bax Bcl-2-associated X protein, MOMP mitochondrial outer membrane permeabilization, Casp caspase, MNDA myeloid nuclear differentiation antigen, cyto c cytochrome c, Apaf-1 apoptotic protease-activating factor 1, HtrA2 serine protease HTRA2, SMAC diablo IAP-binding mitochondrial protein, ARTS1 endoplasmic reticulum aminopeptidase 1, XIAP E3 ubiquitin-protein ligase XIAP, G6P glucose-6-phosphate, G6PT glucose-6-phosphate transporter, G6PC3 glucose-6-phosphatase-β, Glu glucose, ER endoplasmic reticulum, PCNA proliferating cell nuclear antigen, PtdIns(3,4,5)P3 phosphatidylinositol (3,4,5)-trisphosphate, PI3Kγ phosphoinositide 3-kinase γ, GPCR G-protein-coupled receptor, Akt protein kinase B, LMP lysosomal membrane permeabilization, CG cathepsin G, CD cathepsin D, PR3 proteinase 3, HIF hypoxia-inducible factor, FIH factor inhibiting HIF, PHD prolyl hydroxylases, pVHL von Hippel Lindau protein.

Fig. 2. Extracellular modulators of neutrophil apoptosis.

This figure focuses on recently published extrinsic modulators of neutrophil apoptosis. a Caspase-8-activated Bid and the executioner Bax/Bak promote Fas-induced neutrophil apoptosis. b–c G-CSF mainly targets Mcl-1 to postpone neutrophil apoptosis, but GM-CSF upregulated Bcl-xL to be the main guardian. d RvE1, as an endogenous lipid mediator, promotes ROS generation and apoptotic caspases activation, and simultaneously negatively regulates ERK- and Akt-mediated anti-apoptotic signals, thereby predisposing neutrophils to phagocytosis-induced apoptosis. e–f Physiological doses of estradiol and progesterone delay neutrophil apoptosis by reducing cyto c release and subsequent caspase activation. g Adiponectin reduces neutrophil apoptosis by stabilizing Mcl-1 and decreasing caspase-3 cleavage. It also activates MAPK, ERK 1/2, Akt, and AMPK signaling. h The interaction between vitronectin and β1/β3/β5 integrins activates Akt and ERK1/2 to diminish neutrophil apoptosis, independently of p38 signaling. i PD-L1 is upregulated in sepsis patients’ neutrophils and activates PI3K/Akt signaling to delay septic neutrophil death. j–m Hypoxia regulates HIF family proteins to delay neutrophil apoptosis. (By Figdraw: PPRSAd2e22). ROS reactive oxygen species, Bim Bcl-2-interacting mediator of cell death, Noxa phorbol-12-myristate-13-acetate-induced protein 1, Puma Bcl-2-binding component 3, Bid BH3-interacting domain death agonist, Mcl-1 myeloid leukemia cell differentiation protein Mcl-1, Bcl-xL Bcl-2-like protein 1, Bak Bcl-2 homologous antagonist/killer, Bax Bcl-2-associated X protein, MOMP mitochondrial outer membrane permeabilization, G-CSF granulocyte-colony stimulating factor, GM-CSF granulocytemacrophage colony-stimulating factor, XIAP E3 ubiquitin-protein ligase XIAP, RvE1 Resolvin E1, BLT1 leukotriene B4 receptor, MAPK mitogen-activated protein kinase, AMPK adenosine monophosphate-activated protein kinase, ERK extracellular signal-regulated kinase, Akt protein kinase B, HIF hypoxia-inducible factor, FIH factor inhibiting HIF, PHD prolyl hydroxylases, pVHL von Hippel Lindau protein.

Fig. 3. GSDME-mediated neutrophil pyroptosis and its potential regulatory factors.

In aging neutrophils, proteinase 3 (PR3), released through lysosomal membrane permeabilization (LMP), cleaves procaspase-3. Activated caspase-3 then cleaves GSDME to trigger pyroptosis. GSDMD is also cleaved by neutrophil elastase (NE) or cathepsin G (CG) released by LMP, but instead of causing pyroptosis by forming pores on the cell membrane, GSDMD-NT perforates granules to amplify LMP. Different death modes and post-death fates of neutrophils determine inflammatory responses. Given that GSDME-mediated neutrophil pyroptosis seems to be a promising target, various regulatory factors at different levels are summarized. Of note, the above mechanisms are mainly studied in other cell types and remain to be verified in neutrophils. (By Figdraw: AAAYTbd5df). GSDMD gasdermin D, GSDME gasdermin E, LMP lysosomal membrane permeabilization, NE neutrophil elastase, PR3 proteinase 3, DAMPs damage-associated molecular patterns, PMR plasma membrane rupture, LAND-V large aging neutrophil-derived vesicles, SP1 specificity protein 1, STAT3 signal transducer and activator of transcription 3, 2- BP, 2-bromopalmitate Sc S-(2-succinyl)cysteine, Pa palmitoylation, GlcNAc-6P N-acetylglucosamine-6-phosphate, AMPK adenosine monophosphate-activated protein kinase, TNFSF15 tumor necrosis factor superfamily member 15, Ph phosphorylation.