Table 1 Role of neutrophils and neutrophil-derived components in different chronic inflammatory diseases
From: Neutrophils as critical orchestrators of chronic inflammation
Chronic inflammatory disease | In vitro/murine (model) / human | Sample type/experimental set-up | Findings concerning neutrophils | References |
|---|---|---|---|---|
RA | -In vitro | -Plasma and synovial fluid neutrophils from patients with RA | -Spontaneous NET formation | |
-Healthy control human neutrophils | -Release of PAD2/4 upon NET release | [118] | ||
-Synovial fibroblasts from patients with RA | -NET uptake by synovial fibroblasts is mediated by TLR9 | [121] | ||
-RA neutrophils | -IL-33 induces NET formation by RA neutrophils | [122] | ||
-RA synovial fibroblasts | -NETs are taken up by synovial fibroblast through TLR9 and induce IL-33 production | [122] | ||
-T cells harvested from the peripheral blood of patients with ACPA + RA | -Cryptic epitopes presented in the MHCII context activate ACPA + T cells | [125] | ||
-Incubation of osteoblasts with NETs | -NETs induce osteoclastogenesis through upregulation of the RANKL/OPG ratio (TLR4/9 mediated) | [129] | ||
-Co-culture of neutrophils with human gingival-derived stem cells (with or without COX2 gene silencing) | -The COX2-mediated inhibition of neutrophil NET release occurs through the activation of PKA which inhibits ERK | [130] | ||
-RA synovial fluid neutrophils | -Increased ROS production independent of priming | [49] | ||
-Healthy control human neutrophils | -Soluble immune complexes activate only primed human neutrophils | [49] | ||
-RA peripheral blood neutrophils | -Increased expression of anti-apoptotic proteins | [134] | ||
-RA synovial fluid neutrophils | -Neutrophils from the synovial fluid only undergo apoptosis when incubated with synovial fluid that has high levels of HIF-1α | [140] | ||
-RA synovial fluid neutrophils | -FAP-α activates PI3K, stimulating NOX2-dependent ROS production thereby inducing necroptosis | [151] | ||
-Peripheral blood RA neutrophils | -Decreased levels of NLRP3 with increased levels of caspase-1 | [154] | ||
-Whole blood protein expression from patients with active RA | -Increased levels of NLRP3, ASC and caspase-1 | [155] | ||
-Healthy control neutrophils | IL-18 primes neutrophils, upregulates expression of CD11b and FPR1, increases levels of intracellular calcium, activates the p38 MAPK signaling pathway and induces ROS production and NE release | [156] | ||
-Synovial fluid RA neutrophils | -Increased expression of LC3 | [157] | ||
-Peripheral blood RA neutrophils | -Increased autophagosome formation | [157] | ||
-Peripheral blood RA neutrophils | -Increased autophagosome formation | [158] | ||
-Murine (CIA) | -X-ray and H&E staining of knees and ankle joint | -Treatment with a therapeutic ACPA inhibits NET-induced tissue damage | [120] | |
-Murine (HLA-DRB1*04:01) | -Quantification of serum ACPA levels | -NETs are taken up and presented by synovial fibroblasts to T cells eventually resulting in the generation of ACPAs | [121] | |
-Murine (CAIA) | -Modified ELISA to measure citH3-DNA in the serum of these mice | -IL-33 stimulates NET release | [122] | |
-Murine (Tlr2-/-) | -qPCR and flow cytometry | -NET histones stimulate the release of IL-17 by Th17 cells through TLR2 | [123] | |
-Murine (HLA-DRB1*04:01) | - The tibiofemoral compartment (TRAP staining) | - Carbamylated NETs induced osteoclastogenesis | [127] | |
-Murine (Micl−/ −) | -Immunofluorescence and sytox green staining | -Increased NET formation in these mice due to loss of negative feedback through MICL | [128] | |
-Murine (AIA) | -Histology and CT (bone loss) | -NETs induce osteoclastogenesis | [129] | |
-Murine (STIA) | -Immunofluorescence, clinical score, gene silencing and flow cytometry | -Human gingival-derived mesenchymal stem cells release prostaglandin E2 which decreases NET formation in neutrophils. | [130] | |
-Mice (Ncf1-/-) | -Neutrophil recruitment, gene expression, flow cytometry | -Mice deficient in NOX2 showed higher levels of Cxcl2, Cxcl3 and Cxcl10 as well as Mmp3 alongside decreased expression of PD-L1 | [132] | |
-Murine (CIA) | -Arthritis score, paw swelling, recruited neutrophils | -Inhibition of NOX2 resulted in the development of arthritis | [133] | |
-Murine (CIA) | -Arthritis severity | -In early RA, inhibition of TIM-4 worsened arthritis | [144] | |
-Murine (CAIA) | -Arthritis severity | -In established RA, inhibition of TIM-4 improved arthritis | [144] | |
-Murine (Tyro3-/-, Axl -/-, Mertk -/-) | -Levels of inflammatory cytokines and arthritis assessment | -KO of Tyro3 improved inflammation and decreased the levels of inflammatory cytokines, opposite findings for Axl and Mertk KO mice | [143] | |
-Murine (Elmo1-/-) | -Arthritis assessment, bone degradation and neutrophil recruitment | -ELMO1, involved in efferocytosis, promotes inflammatory arthritis | [145] | |
-Murine (CIA) | -Loss of Rac1 function | -Rac1, which works downstream of ELMO1 also promotes arthritis | [144] | |
-Murine (STIA) | -Flow cytometry and arthritis scores | -Less neutrophil infiltration and reduced inflammation upon treatment with anti-SIRPa agonistic antibody | [146] | |
-Murine (Ifng-/-) | -Measurment of necroptosis markers and severity of inflammation | - Increased levels of MLKL, RIPK1, and RIPK3, along with more severe joint damage and hyperinflammation150 | [152] | |
-Human | -Synovial fluid | -Increased levels of IL-33 | [122] | |
-Frequency of albumin carbamylation correlates with synovial fluid MPO activity | [126] | |||
-carbamylated NET proteins are increased | [127] | |||
-Plasma | -Cell-free nucleosomes as a potential diagnostic biomarkers | [115] | ||
-Carbamylated NET proteins are increased | [127] | |||
-Serum | [117] | |||
-Synovial fluid | -Cell-free nucleosomes as a potential diagnostic biomarkers | [128] | ||
-Synovial fluid | -Presence of anti-MICL antibodies | |||
-Synovial fluid | -Increased levels of G-CSF, GM-CSF, IL-1β, TNF, IFN-α and IFN-γ | |||
-Peripheral blood | -Adenosin and lactoferrin are upregulated and regulate apoptosis | [147] | ||
[148] | ||||
-Serum | -Ferrous ion levels correlating with DAS28 scores | [153] | ||
-Synovial fluid | -Decreased levels of glutathione and GPX4 | [158] | ||
-Increased levels of IL-18 and caspase –1 | ||||
-Increased levels of IL-6, IL-10, CCL2 and CXCL8, inducing autophagy | ||||
Atherosclerosis | -Murine (Apoe−/−) | -Intravital imaging | -Neutrophil infiltration during early atherosclerosis | [163] |
-Murine (Apoe−/−) | -Intravital imaging | -High neutrophil counts in rupture prone lesions | [164] | |
-Murine (Lysmgfp/gfpApoe-/-) | -Intravital imaging | -Luminal adherence and NETs release at atherosclerotic prone regions | [168] | |
-Murine (ApoE/PR3/NE−/−) | - Intravital imaging, ELISA,.. | - NET-mediated priming of macrophages to produce inflammatory cytokines | [78] | |
-Human | - Plasma | -Increased S100A12 correlating with increased risk of major cardiovascular events | [160] | |
-Immunohistochemistry carotid plaques | -High neutrophil counts in rupture prone atherosclerotic lesions | [165] | ||
-Immunohistochemistry | - High NETs count in complicated coronary plaque segments | [172] | ||
IBD | -In vitro | - Incubation of CCD-18Co cells (human fibroblast cell line derived from colon tissue) with NGAL | - NGAL mediated induction of profibrotic phenotype in CCD-18Co cells (data also validated in mice with DSS-induced colitis) | [177] |
- Incubation of butyrate with neutrophils from patients with IBD | -Reduced production of inflammatory mediators (e.g. IL-6, TNF, S100A8/A9, LCN2,…) | [199] | ||
-Murine (PAD4-/-) | - Western blot,… | -PAD4 mediated citrullination of CKMT1 exacerbating mucosal inflammation in IBD | [181] | |
-Human | -Faecal samples | - S100A8/A9 used as biomarker for disease activity | [174] | |
- Immunohistochemistry colon biopsies | -Increased levels of PAD4 | [180] | ||
- Blood and biopsies | -Correlation between MPO concentrations and disease activity | [182] | ||
-Neutrophil-dominant inflammation within corticoid-resistance | [183] | |||
-Increased expression of OSM (mRNA) correlates with poor response to anti-TNF therapy. | [185] | |||
- Potential protective role of CD177+ neutrophils (e.g. rol in maintaining mucosal integrity) | [188] | |||
SLE | In vitro | -HC neutrophils stimulated with SLE plasma samples | -TLR8 is important for the recognition of RNA-containing immune complexes by neutrophils in SLE | [206] |
-Neutrophils from patients with SLE | -Neutrophils and platelets form TLR-7-dependent complexes, inducing NETosis | [195] | ||
-Neutrophils from blood of patients with SLE | -Normal density neutrophils express more CXCL10 and MMP8 but lower CD66b and release less NETs | [208] | ||
-Healthy control neutrophils incubated with SLE serum | -Circulating immune complexes in the serum are responsible for ROS production | [211] | ||
-Neutrophils from the peripheral blood of patients with SLE | -Loss of the inhibitory Gal1- VSTM1 loop in patients with SLE | [216] | ||
-Incubation of HC neutrophils with SLE serum stimulated with GM-CSF | -Decreased apoptosis | [216] | ||
-Incubation of HC neutrophils with SLE serum containing caspase-8 and caspase-9 inhibitors | -Decreased apoptosis | |||
-Neutrophils harvested from patients with SLE incubated with SLE serum | -Increased expression of autoantigens on the cellular surface which bind TLR3,8 and 9 on PBMCs | [54] | ||
-Neutrophils incubated with microparticles from SLE patients | -NETosis was induced | |||
-Dendritic cells incubated with microparticles from SLE patients | -Release of IL-6, TNF and IFN-α | [224] | ||
- Incubation of neutrophils with SLE serum | -FcγR-mediated activation of caspases 1 and 11, activating gasdermin D | [225] | ||
-In vitro incubation of neutrophils with SLE serum | -Expression of GPX4 is regulated through CREM-α | [226] | ||
[227] | ||||
-Murine (MRL/lpr) | -IV administration of CXCL5 | -IV administration of CXCL5 reduced neutrophil proliferation, activation and recruitment | [210] | |
-Murine (Ncf1m1J) | -Gene expression, ELISA, flow cytometry | -Impaired ROS production, increased expression of IFN type I-regulated genes and increased levels of autoantibodies | [217] | |
- Murine (MRL/lpr) | -Neutrophils isolated from these mice | -SLE IgGs stimulate neutrophil apoptosis through FcγRIII and the upregulation of FasL | [220] | |
-Human | -Whole blood and plasma of patients with SLE | -Improved neutropenia, decreased apoptosis and decreased NETosis | [228] | |
-Blood transcriptomics | -Treatment with belimumab reduced neutrophil counts and activation, neutrophil degranulation was a predictor of response to belimumab treatment | [229] | ||
-Peripheral blood | -Lower levels of CXCL5 compared to HCs | [210] | ||
-Peripheral blood | -Increased levels of oxidized Gal1 and reduced glutathione | [216] | ||
-Peripheral blood | -NETs or NET-related genes HMGB1, ITGB2 and CREB5 as biomarkers | |||
-SLE patients carrying a mutation in the NCF1 gene | -Lower levels of CXCL5 compared to HCs | [210] | ||
-Serum | -Impaired ROS production related to SLE development | [218] | ||
-Macrophages from SLE patients | -Increased levels of FasL, TRAIL and decreased levels of GM-CSF | |||
-Serum | -Reduced CD44 expression and reduced phagocytotic capacity, correlating with anti-nuclear antibodies and disease activity | |||
-Increased levels of TAM receptors | ||||
COPD | -Murine (C57BL/6 J; FVB/N exposed to ciragette smoke) | -Microscopy | -Decreased efferocytosis | [233] |
-Murine (C57BL/6 J) | -ELISA | - Increased NE | [252] | |
-Murine (cGAS-/-/TLR9-/-) | -Immunofluorescence microscopy | - Increased NETs / inducing NETs mediated inflammation | [254] | |
-Murine (Balb/c mice exposed to ciragette smoke) | -BALF | - Increased MMPs (e.g. MMP9) | [248] | |
-Murine (IKTA) | -NE mediated inhibition of elastic fiber assembly in fibroblasts | [255] | ||
-Human | -Exhaled breath condensate | -Increased NE | ||
-Human | -Serum | -Increase of MMPs (e.g. MMP-9) | ||
-Sputum | -Increased NETs | [238] | ||
-Sputum | -Increased neutrophil and CXCL8 counts | |||
-Sputum | -Increased amount of PGP matricryptin (i.e. suggested to interact with CXCR1/2). | [284] | ||
Fibrotic diseases (IPF) | -In vitro | - Co-culture of MMP-9 with human lung embryonic fibroblasts (MRC-5) | - Activation of TGF-β and induces expression of αSMA in fibroblasts | [275] |
-Human | -BALF | -Increased NE & NETs | ||
-BALF | -Increased S100A9 counts | [256] | ||
-BALF & serum | -Increased CXCL8 counts | |||
Fibrotic diseases (MF) | -Human | -Peripheral blood neutrophils | -Increased basal ROS produced by JAK2+ neutrophils | [297] |
-Plasma | -Increased NE | [299] | ||
-Serum | -Increased MMP9/TIMP1 | [300] | ||
-Peripheral blood Neutrophils | -Increased CD24 expression on neutrophils in JAK2+ neutrophils (e.g. resulting in decreased efferocytosis) | [301] | ||
-Bone marrow biopsies | -Increased emperipolesis of neutrophils by megakaryocytes |
