Value of phagocyte function screening for immunotoxicity of nanoparticles in vivo

Figures & data

Figure 1 Receptors linked to main functions of phagocytes.

Note: Activation of these receptors regulates macrophage function, which can be evaluated by a panel of in vitro assays.

Abbreviations: CD14, lipopolysaccharide-binding protein receptor; LPS, lipopolysaccharide; IFN, interferon; TNF, tumor necrosis factor; MHC, major histocompatibility complex; LFA, lymphocyte function-associated antigen; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; NO, nitric oxide.

Table 1 Mechanisms of interference between nonbiodegradable NPs and in vitro assays

Mechanism	Assay(s)	Particle(s)	Reference(s)
Absorbance	Hemolysis	Au, C60	^Citation128^–^Citation130
	LAL	Au, C60	^Citation131
	MTT	Au, CB, C60, Qdots, Ag, AgO, iron oxide, SWCNT	^Citation90, ^Citation92, ^Citation93, ^Citation129, ^Citation132^–^Citation136
	WST-1	Iron oxide	^Citation137
	MTS	Al, Qdots	^Citation51, ^Citation97, ^Citation138
	LDH	Au, SiO2, iron oxide, CeO2	^Citation51, ^Citation98, ^Citation135, ^Citation139
Light scattering	MTT, ATP	Carbon nanodiamonds	^Citation140
Dye absorption	MTT	SWCNT, CB, Al, iron oxide	^Citation95, ^Citation141^–^Citation144
	NR	CB, SWCNT, C60, Si, TiO2	^Citation90, ^Citation134, ^Citation141, ^Citation145^–^Citation148
	AB, AK	SWCNT	^Citation146
	CB, WST-1	SWCNT	^Citation145
Enzyme inactivation/inhibition	LDH	Cu, Ag	^Citation149, ^Citation150
	LDH	ZnO	^Citation135
	LDH	Si, Au, Qdots	^Citation96
	LDH	Au	^Citation151
	AK	PS	^Citation105
Enzyme adsorption	LDH	Cu, Qdots, TiO2	^Citation93, ^Citation95, ^Citation133, ^Citation149, ^Citation152, ^Citation153
Reduction/enzymatic activity	MTT	Si, SWCNT, C60, TiO2	^Citation91, ^Citation95, ^Citation129, ^Citation145, ^Citation148, ^Citation152, ^Citation154, ^Citation155
	AB	Si	^Citation148
	AK	SWCNT	^Citation146
Prevention of reduction	MTT	Zn	^Citation93
Oxidation	H2DCF	CB	^Citation135
	Hemoglobin	Iron oxide	^Citation128
Protein binding	Cytokines	CB, SWCNT, iron oxide, Cu, SiO2, Al2O3, CeO2, NiO2, TiO2	^Citation93, ^Citation135, ^Citation141, ^Citation146, ^Citation156^–^Citation159
Increase enzymatic activity	LAL	Iron oxide	^Citation131
	Hemoglobin	PS, SWCNT	^Citation129, ^Citation146
Physical interaction	TB, calcein AM, live/dead	SWCNT, C60, CB, Qdots	^Citation90
	COMET	Ge	^Citation160
Quenching of fluorescence	H2DCF	CB, SiO2, SiO2-iron	^Citation161, ^Citation162
	LDH	CB, SWCNT, C60, Qdots	^Citation90
	Calcein AM/EthD-1	CB, SWCNT	^Citation90
Increase of fluorescence	H2DCF	Au, iron oxide, TiO2, C60, SiO2, CB, SWCNT	^Citation91^–^Citation95
	PI	Qdots, PS	^Citation95
	Calcein AM/EthD-1	CB, iron oxide	^Citation91
	AB	CB, SWCNT, TiO2, Qdots	^Citation90, ^Citation97, ^Citation145
	Resazurin	CoO	^Citation51
	COMET	TiO2, CuO	^Citation163
Increase of luminescence	Phagocytosis	Qdots	^Citation130
	ATP	SiO2	^Citation139
Quenching of luminescence	Phagocytosis	Au	^Citation129, ^Citation131
Aggregation	Platelet aggregation	Au, C60	^Citation129

Abbreviations: NPs, nanoparticles; Au, gold; C₆₀, C₆₀ fullerenes; LAL, limulus amebocyte lysate; CB, carbon black; Qdots, CdSe quantum dots; Ag, silver; SWCNT, single-walled carbon nanotube; WST-1, water soluble tetrazolium salt; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium); Al, aluminum; LDH, lactate dehydrogenase; SiO₂, silica; CeO₂, cerium oxide; ATP, adenosine triphosphate; NR, neutral red; TiO₂, titanium dioxide; AB, alamarBlue; AK, adenylate kinase; Cu, copper; ZnO, zinc oxide; PS, polystyrene; Zn, zinc; H₂DCF, dihydrodichlorofluorescein; Al₂O₂, aluminum oxide; NiO₂, nickel oxide; TB, trypan blue; AM, acetoxymethylester; Ge, germanium; EthD-1, ethidium homodimer 1; PI, propidium iodide; CoO, cobalt oxide; CuO, copper (II) oxide.

Table 2 Effects of NPs after inhal, IN, IG, IP, IV, oral, oroph, and SC application, and ID and IT in normal animals and in animal models (Model)

Particle	Size (nm)	Application	Model	Effect	Reference(s)
Polystyrene	25–50	IT		Lung inflammation	^Citation164
	68	IT	Coupled antigen	Stimulation of antigen response	^Citation165
	40	ID	OVA	Increased sensitization	^Citation166
	58	IT	OVA	Increased sensitization	^Citation167
	100	SC	OVA	Increased sensitization	^Citation168
	20, 50, 100	ID	Atopic dermatitis	Aggravation of inflammation	^Citation169
SWCNT	1–2	Oroph		Decreased lung clearance of bacteria	^Citation170
	1–2	IT		Proinflammatory cytokine secretion	^Citation171
	1–2	IT	OVA	Increased sensitization	^Citation172
	1–2	Inhal, SC	OVA	Increased sensitization	^Citation113
	1–2	IT	LPS	Aggravation of inflammation	^Citation173
DWCNT	2	IN		Proinflammatory cytokine secretion	^Citation174
MWCNT	20–30	SC		Proinflammatory cytokine secretion	^Citation175
	10–20	Inhal		Proinflammatory cytokine secretion	^Citation176
	12.5–25	Oroph		Lung inflammation	^Citation177
	20–30	IT		Proinflammatory cytokine secretion	^Citation178
	25	IV		Proinflammatory cytokine secretion	^Citation179
	90	IP		Proinflammatory cytokine secretion	^Citation180
	67	IT	OVA	Increased sensitization	^Citation181
	10–50	Inhal, SC	OVA	Increased sensitization	^Citation113
	30–50	Inhal	OVA	Increased sensitization	^Citation182
	67	IT	LPS	Aggravation of lung inflammation	^Citation173
	10–50	IT	LPS	Aggravation of inflammation	^Citation183
Ag	10	ID		Erythema	^Citation8
	18	Inhal		Lung inflammation	^Citation184
	18	Inhal		Lung inflammation	^Citation185
	20	IV		Suppressed immune response to KLH immunization	^Citation187
	22, 42, 71	Oral		Increased TGF-β levels	^Citation186
	52	IT		Proinflammatory cytokine secretion	^Citation12
	33	IN	OVA	Increased sensitization	^Citation188
Au	50	IT		Lung inflammation	^Citation189
	50, not 10	IP		Proinflammatory cytokine secretion	^Citation190
	21	IP		Anti-inflammatory action in adipose tissue	^Citation108
	15	Oroph	TDI	Aggravation of asthma	^Citation191
	5, 15	IP	IL-1β inflammation	Decrease of inflammation	^Citation109
Iron oxide	5.3	IT		Lung inflammation and allergic response	^Citation193
	20	IV		Proinflammatory cytokine secretion	^Citation194
	36	IT		Lung inflammation and cytokine secretion	^Citation192
	58	IV		Decreased OVA-specific antigen production	^Citation195, ^Citation196
	43	IT	OVA	Increased sensitization	^Citation197, ^Citation198
	35	IT	OVA	Increased sensitization	^Citation199
SiO2	10	IT		Lung inflammation	^Citation200
	12	IP		Proinflammatory cytokine secretion	^Citation13
	30, 70	IP		Proinflammatory cytokine secretion	^Citation201
	15	IV		Proinflammatory cytokine secretion	^Citation202
	70	IV		Proinflammatory cytokine secretion	^Citation203
	30, 70, 100	ID	Atopic dermatitis	Aggravation of inflammation	^Citation204
	10–20	IT	OVA	Increased sensitization	^Citation205
TiO2	2–5	Inhal		Lung inflammation	^Citation207
	5	IP		Proinflammatory cytokine secretion	^Citation215
	5.5	IG		Infiltration of immune cells in spleen	^Citation213
	8–10	IN		Lung inflammation	^Citation206
	20	ID, not oral		Immune activation	^Citation8
	20	Inhal		Lung inflammation	^Citation208
	20	IT		Lung inflammation	^Citation209
	25	IT		Proinflammatory cytokine secretion	^Citation210
	25	IT		Lung inflammation	^Citation211
	15, 28	IT		Lung inflammation	^Citation212
	30–40	IT		Lung inflammation	^Citation200
	66	Oral		Proinflammatory cytokine secretion	^Citation14
	20	IG		Proinflammatory and allergic cytokine secretion	^Citation214
	14, 29	Inhal	OVA	Increased sensitization	^Citation217
	15	Oroph	TDI	Aggravation of asthma	^Citation191
	20	IP	LPS	Aggravation of lung inflammation	^Citation218
	28	Inhal	OVA	Increased sensitization	^Citation216
ZnO	10	Inhal		Lung inflammation	^Citation219
	<10	IT		Lung inflammation	^Citation200
	21	Oral		No effect on oral tolerance to OVA	^Citation107
	21	IP	OVA	Increased sensitization	^Citation114
	55	IP	OVA	Increased sensitization	^Citation115

Abbreviations: NPs, nanoparticles; inhal, inhalation; IN, intranasal; IG, intragastral; IP, intraperitoneal; IV, intravenous; oroph, oropharyngeal; SC, subcutaneous; ID, intradermal; IT, intratracheal instillation; OVA, ovalbumin; SWCNT, single-walled carbon nanotube; LPS, lipopolysaccharide; DWCNT, double-walled carbon nanotube; MWCNT, multiwalled carbon nanotube; Ag, silver; TGF, transforming growth factor; KLH, keyhole limpet hemocyanin; Au, gold; TDI, toluene diisocyanate; IL, interleukin; SiO₂, silica; TiO₂, titanium dioxide; ZnO, zinc oxide.

Table 3 Immune effects in isolated phagocytes, either after in vivo treatment with nanoparticles (ex vivo) or by in vitro treatment

Particle	Effects
	Ex vivo	In vitro
Polystyrene		Proinflammatory cytokine secretion^Citation81
		Increased respiratory burst^Citation81
		Neutrophilic granulocyte activation^Citation81
MWCNT		Proinflammatory cytokine secretion^Citation220
		Inhibition of DC maturation^Citation118
SWCNT		Decreased chemotaxis^Citation221
		Decreased phagocytosis^Citation221
Ag	Proinflammatory cytokine secretion after IT application^Citation8	Proinflammatory cytokine secretion^Citation222^–^Citation224
	Proinflammatory cytokine secretion after inhalation^Citation225	Decreased phagocytosis^Citation12
	Proinflammatory cytokine secretion after oropharyngeal application^Citation226	Increased respiratory burst^Citation227
	Proinflammatory cytokine secretion after oral application^Citation186	Decreased NO production^Citation228
		Neutrophilic granulocyte activation^Citation117
Au		Proinflammatory cytokine secretion^Citation112,Citation229,Citation230
		No increased cytokine secretion^Citation110,Citation111
		No effect on DC maturation, no activation^Citation94,Citation112
Iron oxide	Proinflammatory cytokine secretion after IT application^Citation199,Citation231	Proinflammatory cytokine secretion^Citation232
	Upon LPS challenge, decreased cytokine secretion after IT application^Citation233	Decreased phagocytosis^Citation234
		Increased NO production with and without
		LPS challenge^Citation233,Citation234
		No effect on DC maturation^Citation94
SiO2	Increased NO production after IT application^Citation235	Proinflammatory cytokine secretion^Citation13,Citation236,Citation237
		Activation of DC^Citation119
TiO2	Proinflammatory cytokine secretion after IT application^Citation235,Citation238,Citation239	Proinflammatory cytokine secretion^Citation240
	Proinflammatory cytokine secretion after IG application^Citation10	Decreased chemotaxis^Citation241
		Decreased phagocytosis^Citation12
	Increased NO production after IT application^Citation235,Citation239	Increased respiratory burst^Citation242
	Decreased chemotaxis after IT application^Citation235,Citation239	Activation of DC^Citation119
ZnO	Decrease of cytokine secretion after oral application^Citation116	Proinflammatory cytokine secretion^Citation243^–^Citation245
	Proinflammatory cytokine secretion after IT application^Citation199	Decreased chemotaxis^Citation241
	Proinflammatory cytokine secretion after inhalation^Citation11,Citation219	Decreased phagocytosis^Citation12
		Increased respiratory burst^Citation246

Abbreviations: MWCNT, multiwalled carbon nanotube; DC, dendritic cells; SWCNT, single-walled carbon nanotube; Ag, silver; IT, intratracheal instillation; NO, nitric oxide; Au, gold; LPS, lipopolysaccharide, SiO₂, silica; TiO₂, titanium dioxide; IG, intragastral; ZnO, zinc oxide.

Table 4 Overview of nanoparticle actions on phagocyte functions

Particles	Cytokine secretion		Chemotaxis		Phagocytosis		Respiratory burst		NO generation		Degranulation		DC maturation
	Ex vivo	In vitro	Ex vivo	In vitro	Ex vivo	In vitro	Ex vivo	In vitro	Ex vivo	In vitro	Ex vivo	In vitro	Ex vivo	In vitro
Polystyrene		↑						↑				↑
MWCNT		↑												↓
SWCNT				↓		↓
Ag	↑	↑				↓		↑		↓		↑
Au		↑ −												–
Iron oxide	↑	↑				↓				↑				–
SiO2		↑							↑					↑
TiO2		↑	↓	↓		↓		↑	↑					↑
ZnO	↑ ↓	↑		↓		↓		↑

Notes: Red arrow: increase; black arrow: decrease; –: no change.

Abbreviations: NO, nitric oxide; DC, dendritic cell; MWCNT, multiwalled carbon nanotube; SWCNT, single-walled carbon nanotube; Ag, silver; Au, gold; SiO₂, silica; TiO₂, titanium dioxide; ZnO, zinc oxide.

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