Per- and polyfluoroalkyl substances alter innate immune function: evidence and data gaps

Figures & data

Figure 1. Chemical structures of PFAS discussed in this review. Structures were made using ChemDraw professional (v16.0.1.4) and standard international union of pure and applied chemistry (IUPAC) nomenclature. Structures are organized according to a previously described scheme (Wang et al. 2017).

Table 1. Summary of innate immune modulation associated with exposure to PFASs in humans, primary human leukocytes, and human cell lines.

PFAS	CAS-RN	Immunophenotyping	Cytokine alteration	Functional endpoints	Citations
PFOA	335-67-1	↓ neutrophils,	↑↓ TNFɑ,	↑↓ activation of NF-κB	(Corsini et al. 2011, 2012; Singh et al. 2012; Bassler et al. 2019; Abraham et al. 2020; Lopez-Espinosa et al 2021; Zhao et al. 2022)
		↑ monocytes	↑ IFNγ,
			↑↓ IL-6,
			↑↓ IL-8,
			↓ IL-10,
			↓ IL-4,
			↑ IL-1β
PFOS	1763-23-1	↓ neutrophils,	↓ TNFɑ,	↓ NK cell cytolysis	(Brieger et al. 2011; Corsini et al. 2011, 2012; Singh et al. 2012; Bassler et al. 2019, Goodrich et al. 2021, Lopez-Espinosa et al. 2021, Zhao et al. 2022)
		↑↓ monocytes	↓ IL-6,
			↓ IL-8,
			↓ IL-10,
			↓ IL-4,
			↑ IL-1β
PFNA	375-95-1	↓ neutrophils,	↑ IFNγ,	–	(Bassler et al. 2019; Goodrich et al. 2021; Lopez-Espinosa et al. 2021)
		↓ eosinophils,	↓ IL-8
		↓ NK cells
PFDA	335-76-2	↓ monocytes	–	–	(Goodrich et al. 2021)
PFOSA	754-91-6	–	↓ IL-6,	–	(Corsini et al. 2012)
			↓ IL-8,
			↓ IL-10,
			↓ IL-4
PFHxS	355-46-4	↑ monocytes,	↓ TNFɑ	–	(Bassler et al. 2019; Lopez-Espinosa et al. 2021)
		↓ eosinophils
PFHxA	307-24-4	–	–	↓ ROS production	(Phelps et al. 2023)
PFBS	375-73-5	–	↓ IL-6,	–	(Corsini et al. 2012)
			↓ IL-8,
			↓ IL-10,
			↓ IL-4
GenX	62037-80-3	–	–	↓ ROS production	(Phelps et al. 2023)
8:2 FTOH	678-39-7	–	↓ IL-6,	–	(Corsini et al. 2012)
			↓ IL-8,
			↓ IL-10,
			↓ IL-4
Perflubron	423-55-2	–	–	↓ chemotaxis,	(Fernandez et al. 2001)
				↓ phagocytosis
Perfluoro decalin	306-94-5	–	–	↓ chemotaxis,	(Virmani et al. 1984)
				↓ phagocytosis,
				↓ ROS production
PFTBA	311-89-7	–	–	↓ phagocytosis	(Virmani et al. 1983)
Mixtures	–	↑ basophils	–	–	(Oulhote et al. 2017)

Table 2. Summary of innate immune modulation by exposure to PFASs in experimental mammals.

PFAS	CAS-RN	Immunophenotyping	Cytokine alteration	Functional endpoints	Citations
PFOA	335-67-1	↑↓ macrophages,	↑↓ TNFɑ,	↑↓ NK cell cytolysis,	(Keil et al. 2008; Peden-Adams et al. 2008; Dong et al. 2009, 2011; Qazi et al. 2009, 2010a, 2012; Zheng et al. 2009; Han et al. 2018a, 2018b; Singh et al. 2012; Vetvicka and Vetvickova 2013; Shane et al. 2020; Guo et al. 2021; Tian et al. 2021)
		↓ neutrophils,	↑↓ IL-6,	↑↓ activation of NF-κB,
		↑ NK cells,	↓ IL-4,	↓ phagocytosis
		↑ granulocytes,	↓ IFNγ,
		↑ myeloid suppressor cells,	↑ IL-1β
		↓ myeloid cells
PFOS	1763-23-1	↑↓ macrophages,	↑↓ TNFɑ,	↑↓ NK cell cytolysis,	(Keil et al. 2008; Peden-Adams et al. 2008; Zheng et al. 2009; Qazi et al. 2009, 2010b, 2012; Dong et al. 2009, 2011; Vetvicka and Vetvickova 2013; Han et al. 2018a, 2018b; National Toxicology Program (NTP) 2019)
		↓ myeloid cells,	↑↓ IL-6,	↑ inflammasome activation,
		↓ neutrophils	↓ IL-4,	↓ phagocytosis
			↓ IFNγ,
			↑ IL-1β,
PFNA	375-95-1	↓ macrophages,	↑TNFɑ	–	(Fang et al. 2008; Rockwell et al. 2013, 2017)
		↓ neutrophils,
		↓ NK cells,
		↑ phagocytes,
PFDA	335-76-2	↓ macrophage,	–	↓ phagocytosis	(Frawley et al. 2018)
		↓ NK cells
PFUnDA	2058-94-8	↓ macrophages	–	↓ phagocytosis	(Bodin et al. 2016; Berntsen et al. 2018)
PFTBA	311-89-7	↓ neutrophils	–	–	(Virmani et al. 1983)
PFBA	375-22-4	↑ neutrophils,	–	–	(Weatherly et al. 2021)
		↑ dendritic cells,
		↑ eosinophils,
		↑ NK cells
PFMOBA	863090-89-5	↓ NK cells	–	–	(Woodlief et al. 2021)
8:2 FTOH	678-39-7	–	↓ TNFɑ,	–	(Kong et al. 2019)
			↓ IL-6,
			↓ IL-1β
6:2 FTCA	53826-12-3	–	↑ TNFɑ,	↑ activation of NF-κB	(Sheng et al. 2017)
6:2 FTSA	27619-97-2	–	↑ TNFɑ,	↑ activation of NF-κB	(Sheng et al. 2017)
			↑ IL-1β,
			↑ IL-10,
			↑ IL-6
Mixtures	–	–		↓ phagocytosis	(Brieger et al. 2011)

Table 3. Summary of innate immune modulation by exposure to PFASs in zebrafish.

PFAS	CAS-RN	Cytokine alteration	Functional endpoints	Citations
PFOA	335-67-1	↓ IL-1β,	↓ chemotaxis	(Zhang et al. 2014; Pecquet et al. 2020)
		↑↓ IL-4
PFOS	1763-23-1	↑ IL-8,	↑ granulomas,	(Keiter et al. 2012; Liu et al. 2013; Guo et al. 2019)
		↑ IL-6,	↑ ROS production,
		↑ IL-1β,	↑ lysozyme activity
		↑ TNFɑ
6:2 FTAB	34455-29-3	↑ IL-8,	–	(Shi et al. 2018)
		↑ IL-1β
		↑ TNFɑ
F-53B	756426-58-1	↑ IL-1β	↑ ROS production	(Liu et al. 2021)
OBS	70829-87-7	↑ IL-1β,	–	(Huang et al. 2021)
		↑ IL-8
PFHxA	307-24-4	–	↓ ROS production	(Phelps et al. 2023)
GenX	62037-80-3	–	↓ ROS production	(Phelps et al. 2023)

Table 4. Summary of innate immune modulation by exposure to PFASs in wildlife and ecotoxicological models.

PFAS	CAS-RN	Immunophenotyping	Functional endpoints	Citations
PFOS	1763-23-1	–	↑ lysozyme activity (striped bass, chickens)	(Peden-Adams et al. 2009; Guillette et al. 2020)
PFHxS	355-46-4	–	↓ ROS production (eagles)	(Hansen et al. 2020)
Mixtures	–	↓ eosinophils (dolphins)	↑ phagocytosis (dolphins), ↓ ROS production (eagles)	(Fair et al. 2013; Hansen et al. 2020)

Figure 2. Visual summary of mechanisms of PFAS toxicity observed in monocytes, microglia, and macrophages. PFAS have been shown to disrupt immune signaling and other pathways in (A) monocytes (Corsini et al. 2011, 2012, 2021; Racchi et al. 2017; Masi et al. 2022), (B) microglia (Yang et al. 2015; Wang et al. 2015; Zhu et al. 2015; Ge et al. 2016; Lin et al. 2022), and (C) macrophages (Chang et al. 2005; Miyano et al. 2012; Kong et al. 2019; Wang, Liu et al. 2021; Tian et al. 2021; Yu et al. 2022; Lee et al. 2022; Wang, Tan, et al. 2023). Black arrows and red lines with a ‘T’ end indicate normal function (activating and inhibiting, respectively). PFAS-induced endpoints for each gene/protein are shown graphically as red up arrows (increase in signal and/or expression), blue down arrows (decrease in signal/expression), dash (no observed change), checkmark (binding between protein and any PFAS observed in vitro), checkmark with question mark (binding between protein and any PFAS suggested in silico, but not demonstrated in vitro). Details are provided in Supplemental Table S1. AIM2: absent in melanoma 2; arg-1: Arginase 1; ASC: Apoptosis-associated speck-like protein containing a CARD; BAK: Bcl-2 homologous antagonist killer; BAX: Bcl-2-associated X protein; BCL-2: B-cell lymphoma 2; BIP: Binding immunoglobulin protein; Casp1: Caspase 1; Casp3: Caspase 3; CCL2: Chemokine ligand 2, also called MCP-1; CXCL1: Chemokine (CXC motif) ligand 1; CD: Cluster of differentiation (multiple types); COX2: Cytochrome c oxidase II; cyt C: Cytochrome C; ERK: Extracellular signal-regulated kinase; H2-Aa: Histocompatibility 2, class II antigen A, alpha; H2-K1: histocompatibility 2, K1, K region; IFNγ: interferon-γ; IκB: nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor; IL: Interleukin (several types); iNOS: Inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; KO: knockout; LPS: Lipopolysaccharide; MAPK: Mitogen-activated protein kinase; MMP9: Matrix metallopeptidase-9; mtDNA: Mitochondrial DNA; NF-κB: Nuclear factor κ-light-chain-enhancer of activated B-cells; NLRP3: NOD-like receptor family pyrin domain containing 3; OPN: Osteopontin; PARP: Poly (ADP-ribose) polymerase; PGE-2: Prostaglandin E₂; PI3K: Phosphoinositide 3-kinase; PKCβ: protein kinase Cβ; PPARα: peroxisome proliferator-activated receptor-α; RACK1: Receptor for activated C kinase 1; RCS: Reactive carbonyl species; ROS: Reactive oxygen species; STAT3: Signal transducer and activator of transcription-3; TNFα: tumor necrosis factor-α.

Figure 3. Visual summary of mechanisms suggested in tissue-level, acellular, and other studies not specifically in innate immune cells. PFAS have been shown to disrupt (A) Toll-like receptor signaling (Singh et al. 2012; Zhang et al. 2014; Zhang et al. 2021; Sheng et al. 2017; Chen et al. 2018; Han et al. 2018b; Castaño-Ortiz et al. 2019; Guo et al. 2019; Shane et al. 2020; Zhang et al. 2020; Zhong et al. 2020; Xie et al. 2021; Huang et al. 2022; Wan et al. 2022; Xu et al. 2022; Liu et al. 2023, Tang et al. 2023) and (B) PPAR signaling (Corsini et al. 2012; Pennings et al. 2016; Sheng et al. 2017; Wu et al. 2017; Rodríguez-Jorquera et al. 2019; Shane et al. 2020; Christofides et al. 2021; Khazaee et al. 2021; Weatherly et al. 2021; Zhang, Dong, et al. 2021; Camdzic et al. 2022, Chen et al. 2022; Evans et al. 2022; Wang et al. 2022; Xu et al. 2022; Sun et al. 2023), but the effect of PFAS on these pathways in innate immune cells remained understudied. Black arrows and red lines with a ‘T’ end indicate normal function (activating and inhibiting, respectively). PFAS-induced endpoints for each gene/protein are shown graphically as red up arrows (increase in signal/expression), blue down arrows (decrease in signal/expression), checkmark (binding between protein and any PFAS observed in vitro), checkmark with question mark (binding between protein and any PFAS suggested in silico, but not demonstrated in vitro). Details are provided in Supplemental Table S1. Abbreviations: CD36: Cluster of differentiation 36; E-FABP: Fatty acid binding protein [epidermal type]; HMGB1: High mobility group box 1 protein; IκB: Nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor; IRAK: IL-1 receptor-associated kinase; MyD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor κ-light-chain-enhancer of activated B-cells; PPAR: Peroxisome proliferator-activated receptor; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor-6.

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