TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration.
Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-α) and different alpha-synuclein (αSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-α display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor κB (NF-κB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight αSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-α and αSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson's disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.
Pubmed ID: 33761362 RIS Download
Research resources used in this publication
- Glial Fibrillary Acidic Protein (Multipurpose) (RRID:AB_10013382) (antibody)
- Donkey anti-Goat IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2535853) (antibody)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (RRID:AB_2536183) (antibody)
- Monoclonal Anti-S-100 (beta-Subunit) antibody produced in mouse (RRID:AB_477499) (antibody)
- Ezrin Antibody (RRID:AB_2100309) (antibody)
- AQP4 Antibody (H-80) (RRID:AB_2274338) (antibody)
- Anti-Glutamine Synthetase, clone GS-6 (RRID:AB_2110656) (antibody)
- Anti-ID3 antibody (RRID:AB_2732885) (antibody)
- Nuclear factor-1 antibody (RRID:AB_2335600) (antibody)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492) (antibody)
- GM130 antibody [EP892Y] (RRID:AB_880266) (antibody)
- NF- B p65 (L8F6) Mouse mAb (RRID:AB_10828935) (antibody)
- Mouse Anti-MHC Class II (HLA-DP) beta 1 Monoclonal Antibody, Unconjugated (RRID:AB_944199) (antibody)
- FITC anti-human HLA-DR, DP, DQ (RRID:AB_2563192) (antibody)
- Human TruStain FcX™ (Fc Receptor Blocking Solution) (RRID:AB_2818986) (antibody)
- Rabbit Anti-Human LAMP2a Polyclonal Antibody, Unconjugated (RRID:AB_775981) (antibody)
- Donkey Anti-Mouse IgG (H+L) Polyclonal Antibody, Alexa Fluor ?? 647 Conjugated (RRID:AB_162542) (antibody)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2536180) (antibody)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_162543) (antibody)
- Alexa Fluor 488 AffiniPure Donkey Anti-Chicken IgY (IgG) (H+L) (RRID:AB_2340375) (antibody)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_141607) (antibody)
- FOXA2-human (RRID:AB_2262810) (antibody)
- Anti-LMX1A antibody - C-terminal (RRID:AB_2827684) (antibody)
- Monoclonal Anti-β-Tubulin III antibody produced in mouse (RRID:AB_477590) (antibody)
- Monoclonal Anti-Actin, α-Smooth Muscle (RRID:AB_476701) (antibody)
- Mouse Anti-Fetoprotein, alpha (AFP) Monoclonal Antibody, Unconjugated, Clone C3 (RRID:AB_258392) (antibody)
- SSEA4 Monoclonal Antibody (eBioMC-813-70 (MC-813-70)), PE (RRID:AB_2534281) (antibody)
- Chicken Anti-Sendai Virus Sendai virus Polyclonal Antibody, Unconjugated (RRID:AB_777877) (antibody)
- TRA-1-81 Monoclonal Antibody (cl.26) (RRID:AB_2533495) (antibody)
- Mouse Anti-Human Nanog Monoclonal Antibody, PE Conjugated (RRID:AB_1645522) (antibody)
Additional research tools detected in this publication
Antibodies used in this publication
- Goat anti-Mouse IgG (H+L), Superclonal Recombinant Secondary Antibody, HRP (RRID:AB_2536163)
- Rabbit Anti-Human LAMP2a Polyclonal Antibody, Unconjugated (RRID:AB_775981)
- Human TruStain FcX™ (Fc Receptor Blocking Solution) (RRID:AB_2818986)
- FITC anti-human HLA-DR, DP, DQ (RRID:AB_2563192)
- Mouse Anti-MHC Class II (HLA-DP) beta 1 Monoclonal Antibody, Unconjugated (RRID:AB_944199)
- NF- B p65 (L8F6) Mouse mAb (RRID:AB_10828935)
- GM130 antibody [EP892Y] (RRID:AB_880266)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492)
- Nuclear factor-1 antibody (RRID:AB_2335600)
- Anti-ID3 antibody (RRID:AB_2732885)
- Anti-Glutamine Synthetase, clone GS-6 (RRID:AB_2110656)
- AQP4 Antibody (H-80) (RRID:AB_2274338)
- Ezrin Antibody (RRID:AB_2100309)
- Monoclonal Anti-S-100 (beta-Subunit) antibody produced in mouse (RRID:AB_477499)
- Glial Fibrillary Acidic Protein (Multipurpose) (RRID:AB_10013382)
- Donkey anti-Goat IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2535853)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (RRID:AB_2536183)
- Donkey Anti-Mouse IgG (H+L) Polyclonal Antibody, Alexa Fluor ?? 647 Conjugated (RRID:AB_162542)
- Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_162543)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (RRID:AB_2536180)
- Alexa Fluor 488 AffiniPure Donkey Anti-Chicken IgY (IgG) (H+L) (RRID:AB_2340375)
- Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_141607)
- FOXA2-human (RRID:AB_2262810)
- Anti-LMX1A antibody - C-terminal (RRID:AB_2827684)
- Monoclonal Anti-β-Tubulin III antibody produced in mouse (RRID:AB_477590)
- Monoclonal Anti-Actin, α-Smooth Muscle (RRID:AB_476701)
- Mouse Anti-Fetoprotein, alpha (AFP) Monoclonal Antibody, Unconjugated, Clone C3 (RRID:AB_258392)
- Chicken Anti-Sendai Virus Sendai virus Polyclonal Antibody, Unconjugated (RRID:AB_777877)
- SSEA4 Monoclonal Antibody (eBioMC-813-70 (MC-813-70)), PE (RRID:AB_2534281)
- TRA-1-81 Monoclonal Antibody (cl.26) (RRID:AB_2533495)
- Mouse Anti-Human Nanog Monoclonal Antibody, PE Conjugated (RRID:AB_1645522)
- Mouse CD40/TNFRSF5 MAb (Clone 1C10) (RRID:AB_358378)
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Telethon Network of Genetic Biobanks (tool)
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Network of non profit association of Italian repositories to form catalogue of biospecimens and associated data. Used to collect, process, preserve and distribute biological samples and related clinical data from individuals affected by rare diseases, their relatives or from healthy control individuals, with standards complying with Italian laws and international recommendations. You may browse sample catalogue by diagnosis or use advanced search option. Request for samples is granted only if project is in agreement with TNGB mission and after receiving signed material transfer agreement form.
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RRID:AB_2536163
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RRID:AB_775981
This polyclonal targets Human LAMP2a - Lysosome Marker
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RRID:AB_2818986
This unknown targets FC receptors
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This monoclonal targets HLA-DR DP DQ
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RRID:AB_944199
This monoclonal targets MHC Class II
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RRID:AB_10828935
This monoclonal targets NF-κB p65
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RRID:AB_880266
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View all literature mentionsSox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
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RRID:AB_2335600
This polyclonal targets NF-1A
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RRID:AB_2732885
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View all literature mentionsAnti-Glutamine Synthetase, clone GS-6 (antibody)
RRID:AB_2110656
This unknown targets
View all literature mentionsAQP4 Antibody (H-80) (antibody)
RRID:AB_2274338
This polyclonal targets AQP4
View all literature mentionsMonoclonal Anti-S-100 (beta-Subunit) antibody produced in mouse (antibody)
RRID:AB_477499
This monoclonal targets S-100 (beta-Subunit)
View all literature mentionsGlial Fibrillary Acidic Protein (Multipurpose) (antibody)
RRID:AB_10013382
This polyclonal targets GFAP
View all literature mentionsDonkey anti-Goat IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_2535853
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (antibody)
RRID:AB_2536183
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey Anti-Mouse IgG (H+L) Polyclonal Antibody, Alexa Fluor ?? 647 Conjugated (antibody)
RRID:AB_162542
This polyclonal targets Mouse IgG (H+L)
View all literature mentionsDonkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_162543
This polyclonal secondary targets IgG (H+L)
View all literature mentionsDonkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 555 (antibody)
RRID:AB_2536180
This polyclonal secondary targets IgG (H+L)
View all literature mentionsAlexa Fluor 488 AffiniPure Donkey Anti-Chicken IgY (IgG) (H+L) (antibody)
RRID:AB_2340375
This polyclonal targets IgY (IgG) (H+L)
View all literature mentionsDonkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (antibody)
RRID:AB_141607
This polyclonal secondary targets IgG (H+L)
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RRID:AB_2827684
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View all literature mentionsMonoclonal Anti-β-Tubulin III antibody produced in mouse (antibody)
RRID:AB_477590
This monoclonal targets β-Tubulin III
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RRID:AB_258392
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RRID:AB_777877
This polyclonal targets Sendai Virus Sendai virus
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RRID:AB_358378
This monoclonal targets Mouse CD40/TNFRSF5 MAb (Clone 1C10)
View all literature mentionsGlial Fibrillary Acidic Protein (Multipurpose) (antibody)
RRID:AB_10013382
This polyclonal targets GFAP
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RRID:AB_2535853
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View all literature mentionsDonkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 647 (antibody)
RRID:AB_2536183
This polyclonal secondary targets IgG (H+L)
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RRID:AB_477499
This monoclonal targets S-100 (beta-Subunit)
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RRID:AB_2274338
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RRID:AB_2110656
This unknown targets
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RRID:AB_2732885
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RRID:AB_2335600
This polyclonal targets NF-1A
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RRID:AB_2665492
This monoclonal targets Sox9
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RRID:AB_880266
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RRID:AB_10828935
This monoclonal targets NF-κB p65
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RRID:AB_944199
This monoclonal targets MHC Class II
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RRID:AB_2563192
This monoclonal targets HLA-DR DP DQ
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RRID:AB_2818986
This unknown targets FC receptors
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RRID:AB_775981
This polyclonal targets Human LAMP2a - Lysosome Marker
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RRID:AB_162542
This polyclonal targets Mouse IgG (H+L)
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RRID:AB_2536180
This polyclonal secondary targets IgG (H+L)
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RRID:AB_162543
This polyclonal secondary targets IgG (H+L)
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RRID:AB_2340375
This polyclonal targets IgY (IgG) (H+L)
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RRID:AB_141607
This polyclonal secondary targets IgG (H+L)
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RRID:AB_2827684
This polyclonal targets LMX1A
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RRID:AB_477590
This monoclonal targets β-Tubulin III
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RRID:AB_476701
This monoclonal targets Actin, α-Smooth Muscle
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RRID:AB_258392
This monoclonal targets alpha-Fetoprotein (AFP)
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RRID:AB_2534281
This monoclonal targets SSEA4
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RRID:AB_777877
This polyclonal targets Sendai Virus Sendai virus
View all literature mentionsTRA-1-81 Monoclonal Antibody (cl.26) (antibody)
RRID:AB_2533495
This monoclonal targets TRA-1-81
View all literature mentionsMouse Anti-Human Nanog Monoclonal Antibody, PE Conjugated (antibody)
RRID:AB_1645522
This monoclonal targets Nanog
View all literature mentions
