Table 1 Neutrophil heterogeneity in... | American Society of Hematology

Table 1

Neutrophil heterogeneity in homeostatic and pathological conditions

Neutrophil subset	Prevalence	Phenotypic properties	Functional properties	Homeostatic/pathological relevance	Reference
CD177⁺	Human: ∼50% of circulating neutrophils	CD177⁺ Proteinase 3	= Apoptosis = transmigration in human peritonitis↓ granule protein mRNA content	CD177 autoantibodies in ANCA-derived vasculitis patients	41,,,-45
“Aged”	Mouse:	CXCR4^highCD62L^lowCD11B^high CD49^high; hypersegmented nucleus; Reduced size and granularity		Regulation of stem cell niche and circadian release of HSPCs to the circulation / Enhanced intravascular inflammation	46,47
	55 ± 14% in ZT5 (clearance from the circulation period)		= Apoptosis
	8 ± 3% in Z17 (release from the circulation period)		↑ Phagocytosis and NETosis
OLFM4⁺	Human: 20-25% of circulating neutrophils	OLFM4 expression in neutrophil-specific granules	= Apoptosis	OLFM4 autoantibodies in ANCA-derived vasculitis patients	48,,,-52
			= Phagocytosis	Enhanced immune response against S aureus and E coli infection in absence of OLFM4
			= Transmigration
			↓ Cathepsin C activity
			OLFM4 + NET formation
TCR⁺	Human: 3-5% of circulating neutrophils	Human: TCRα,β variants	Delayed apoptosis and IL-8 production on CD3/CD28 stimulation	Reduced TCR variants in aged subjects compared to young individuals	53,54
TCR⁺	Human: 3-5% of circulating neutrophils	Mouse: Vα2, Vα5, Vβ1, Vβ16			53,54
Angiogenic	Mouse: 2.8%	CD49d⁺VEGFR1^highCXCR4^high	↑MMP9	Promotes angiogenesis in hypoxic tissue	55,56
Angiogenic	Human: 3.2%	CD49d⁺VEGFR1^highCXCR4^high	↑MMP9	Promotes angiogenesis in hypoxic tissue	55,56
CD62L^dim/CD16^brightCD62L^bright/CD16^dim	Human: 3 hours after LPS administration:	CD62L^bright; CD16^bright; multi-lobular nucleus	CD62L^dim/CD16^bright: -Inhibition of T-cell proliferation through ROS release and dependent on CD11B expression	Potential implication in sepsis-related immunosuppresion	57,58
	CD62L^bright/CD16^bright: 60-70%	CD62L^dim; CD16^bright; CD11C^high; CD11B^high; CD54^high ; hypersegmented nucleus
	CD62L^dim/CD16^bright:20-25%	CD62L^bright; CD16^dim; CD11C^low; CD11B^low; CD54^low ; band-form nucleus
	CD62L^bright/CD16^dim:10-15%
CD63⁺	Human: neutrophils isolated from lung sputum	CD11B^high CD66^high CD63⁺CD80⁺MHC-II⁺	↓ Glutathione activity	Neutrophil elastase-dependent perpetuation of inflammation, infection and progression of cystic fibrosis airway disease	59,60
			↑ Neutrophil elastase activity
			↑ Arg1
IL-13⁺	Not defined	Ring-form nucleus; IL-5; IL-13; IL-33; insulin-like growth factor-1; Resistin-like molecule alpha/FIZZ1; chitinase-like 3.	Priming of macrophages towards alternative or M2 phenotype	Accelerated clearance of nematodes by primed macrophages	61
CD49⁺	Mouse:	PMN-I: CD11B⁻, CD49⁺, TLR2⁺, TLR4⁺, TLR5⁺, TLR8⁺; multilobular nucleus, MPO^high	PMN-I: IL-12, CCL3, classic activation of macrophages	CD49d⁺ neutrophils promote virus-challenged experimental asthma	62,-64
	Sendai virus infection: 50% of BAL neutrophils		PMN-I: IL-12, CCL3, classic activation of macrophages
	MRSA infection: not defined		PMN-II: IL-10, CCL2, alternative activation of macrophages	CD49⁺ but not CD49⁻ neutrophils induce resistance to MRSA infection
	Human:	PMN-II: CD11B⁺, CD49-, TLR2⁺, TLR4⁺, TLR7⁺, TLR9⁺, ring-form nucleus; MPO^low		Association between CD49d⁺ neutrophils and allergic disease in humans
	Non atopic patients: 1.625%; atopic patients: 6.57%
IL-17⁺	Human: ∼70% of circulating neutrophils upon IL-6 and IL-23 stimulation	IL-17A⁺; IL-17ra⁺, RORγt⁺; dectin-2	↑ ROS production	Reduction of Aspergillus fumigatus–mediated keratitis	65
IL-17⁺	Mouse: ∼17% of bone marrow neutrophils on IL-6 and IL-23 stimulation	IL-17A⁺; IL-17ra⁺, RORγt⁺; dectin-2	↑ Increase fungal killing capacity	Reduction of Aspergillus fumigatus–mediated keratitis	65
LDGs	Human:	Mixed population with cells with band, lobular, or myelocyte-like nuclei	↓ Phagocytosis, = MPO, =respiratory burst	Promotion of SLE-associated inflammation: induction of IFN-α production by pDCs through NET release	66,-68
	Healthy donors: ∼17%		↑ IFN-γ; TNF-α
	SLE patients: 1.2-54%		↑ Endothelial cell killing capacity
			↑ NET production
TAN	Not defined	N1 TAN: Met⁺; hypersegmented nuclei	N1 TAN: ↑ tumor cell killing capacity; ↑ NO; ↑ H₂O₂; ↑ TNF-α; ↑ ICAM-1; ↓ arg1; ↓ CCL2, ↓CCL5, ↓VEGF; ↓ MMP9	N1 and N2 TANs inhibit and promotes tumor development, respectively	69,,-72
TAN	Not defined	N2 TAN: Rounded nuclei	N2 TAN: Rounded nuclei ↓ tumor cell killing capacity; ↓ NO; ↓ H₂O₂; ↓ TNF-α; ↓ ICAM-1; ↑ arg1; ↑ CCL2, ↑ CCL5, ↑ VEGF; ↑ MMP9 ↑ S100a8; ↑ S100a9; ↑ Prok2;		69,,-72

Neutrophil subset	Prevalence	Phenotypic properties	Functional properties	Homeostatic/pathological relevance	Reference
CD177⁺	Human: ∼50% of circulating neutrophils	CD177⁺ Proteinase 3	= Apoptosis = transmigration in human peritonitis↓ granule protein mRNA content	CD177 autoantibodies in ANCA-derived vasculitis patients	41,,,-45
“Aged”	Mouse:	CXCR4^highCD62L^lowCD11B^high CD49^high; hypersegmented nucleus; Reduced size and granularity		Regulation of stem cell niche and circadian release of HSPCs to the circulation / Enhanced intravascular inflammation	46,47
	55 ± 14% in ZT5 (clearance from the circulation period)		= Apoptosis
	8 ± 3% in Z17 (release from the circulation period)		↑ Phagocytosis and NETosis
OLFM4⁺	Human: 20-25% of circulating neutrophils	OLFM4 expression in neutrophil-specific granules	= Apoptosis	OLFM4 autoantibodies in ANCA-derived vasculitis patients	48,,,-52
			= Phagocytosis	Enhanced immune response against S aureus and E coli infection in absence of OLFM4
			= Transmigration
			↓ Cathepsin C activity
			OLFM4 + NET formation
TCR⁺	Human: 3-5% of circulating neutrophils	Human: TCRα,β variants	Delayed apoptosis and IL-8 production on CD3/CD28 stimulation	Reduced TCR variants in aged subjects compared to young individuals	53,54
TCR⁺	Human: 3-5% of circulating neutrophils	Mouse: Vα2, Vα5, Vβ1, Vβ16			53,54
Angiogenic	Mouse: 2.8%	CD49d⁺VEGFR1^highCXCR4^high	↑MMP9	Promotes angiogenesis in hypoxic tissue	55,56
Angiogenic	Human: 3.2%	CD49d⁺VEGFR1^highCXCR4^high	↑MMP9	Promotes angiogenesis in hypoxic tissue	55,56
CD62L^dim/CD16^brightCD62L^bright/CD16^dim	Human: 3 hours after LPS administration:	CD62L^bright; CD16^bright; multi-lobular nucleus	CD62L^dim/CD16^bright: -Inhibition of T-cell proliferation through ROS release and dependent on CD11B expression	Potential implication in sepsis-related immunosuppresion	57,58
	CD62L^bright/CD16^bright: 60-70%	CD62L^dim; CD16^bright; CD11C^high; CD11B^high; CD54^high ; hypersegmented nucleus
	CD62L^dim/CD16^bright:20-25%	CD62L^bright; CD16^dim; CD11C^low; CD11B^low; CD54^low ; band-form nucleus
	CD62L^bright/CD16^dim:10-15%
CD63⁺	Human: neutrophils isolated from lung sputum	CD11B^high CD66^high CD63⁺CD80⁺MHC-II⁺	↓ Glutathione activity	Neutrophil elastase-dependent perpetuation of inflammation, infection and progression of cystic fibrosis airway disease	59,60
			↑ Neutrophil elastase activity
			↑ Arg1
IL-13⁺	Not defined	Ring-form nucleus; IL-5; IL-13; IL-33; insulin-like growth factor-1; Resistin-like molecule alpha/FIZZ1; chitinase-like 3.	Priming of macrophages towards alternative or M2 phenotype	Accelerated clearance of nematodes by primed macrophages	61
CD49⁺	Mouse:	PMN-I: CD11B⁻, CD49⁺, TLR2⁺, TLR4⁺, TLR5⁺, TLR8⁺; multilobular nucleus, MPO^high	PMN-I: IL-12, CCL3, classic activation of macrophages	CD49d⁺ neutrophils promote virus-challenged experimental asthma	62,-64
	Sendai virus infection: 50% of BAL neutrophils		PMN-I: IL-12, CCL3, classic activation of macrophages
	MRSA infection: not defined		PMN-II: IL-10, CCL2, alternative activation of macrophages	CD49⁺ but not CD49⁻ neutrophils induce resistance to MRSA infection
	Human:	PMN-II: CD11B⁺, CD49-, TLR2⁺, TLR4⁺, TLR7⁺, TLR9⁺, ring-form nucleus; MPO^low		Association between CD49d⁺ neutrophils and allergic disease in humans
	Non atopic patients: 1.625%; atopic patients: 6.57%
IL-17⁺	Human: ∼70% of circulating neutrophils upon IL-6 and IL-23 stimulation	IL-17A⁺; IL-17ra⁺, RORγt⁺; dectin-2	↑ ROS production	Reduction of Aspergillus fumigatus–mediated keratitis	65
IL-17⁺	Mouse: ∼17% of bone marrow neutrophils on IL-6 and IL-23 stimulation	IL-17A⁺; IL-17ra⁺, RORγt⁺; dectin-2	↑ Increase fungal killing capacity	Reduction of Aspergillus fumigatus–mediated keratitis	65
LDGs	Human:	Mixed population with cells with band, lobular, or myelocyte-like nuclei	↓ Phagocytosis, = MPO, =respiratory burst	Promotion of SLE-associated inflammation: induction of IFN-α production by pDCs through NET release	66,-68
	Healthy donors: ∼17%		↑ IFN-γ; TNF-α
	SLE patients: 1.2-54%		↑ Endothelial cell killing capacity
			↑ NET production
TAN	Not defined	N1 TAN: Met⁺; hypersegmented nuclei	N1 TAN: ↑ tumor cell killing capacity; ↑ NO; ↑ H₂O₂; ↑ TNF-α; ↑ ICAM-1; ↓ arg1; ↓ CCL2, ↓CCL5, ↓VEGF; ↓ MMP9	N1 and N2 TANs inhibit and promotes tumor development, respectively	69,,-72
TAN	Not defined	N2 TAN: Rounded nuclei	N2 TAN: Rounded nuclei ↓ tumor cell killing capacity; ↓ NO; ↓ H₂O₂; ↓ TNF-α; ↓ ICAM-1; ↑ arg1; ↑ CCL2, ↑ CCL5, ↑ VEGF; ↑ MMP9 ↑ S100a8; ↑ S100a9; ↑ Prok2;		69,,-72

arg1, arginase 1; BAL, bronchoalveolar lavage; MMP9, metalloproteinase-9; MPO, myeloperoxidase; MRSA, methicillin-resistant Staphylococcus aureus; NO, nitric oxide; pDCs, plasmacytoid dendritic cells; PMN, polymorphonuclear leukocyte; VEGF, vascular endothelial growth factor; ZT, zeitgeber time; ↑, increase; ↓, decrease; =, no change.

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