---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '19593'
abstract:
- lang: eng
text: Prenatal immune challenges pose significant risks to human embryonic brain
and eye development. However, our knowledge about the safe usage of anti-inflammatory
drugs during pregnancy is still limited. While human induced pluripotent stem
cells (hIPSC)-derived brain organoid models have started to explore functional
consequences upon viral stimulation, these models commonly lack microglia, which
are susceptible to and promote inflammation. Furthermore, microglia are actively
involved in neuronal development. Here, we generate hIPSC-derived microglia precursor
cells and assemble them into retinal organoids. Once the outer plexiform layer
forms, these hIPSC-derived microglia (iMG) fully integrate into the retinal organoids.
Since the ganglion cell survival declines by this time in 3D-retinal organoids,
we adapted the model into 2D and identify that the improved ganglion cell number
significantly decreases only with iMG presence. In parallel, we applied the immunostimulant
POLY(I:C) to mimic a fetal viral infection. While POLY(I:C) exposure alters the
iMG phenotype, it does not hinder their interaction with ganglion cells. Furthermore,
iMG significantly enhance the supernatant’s inflammatory secretome and increase
retinal cell proliferation. Simultaneous exposure with the non-steroidal anti-inflammatory
drug (NSAID) ibuprofen dampens POLY(I:C)-mediated changes of the iMG phenotype
and ameliorates cell proliferation. Remarkably, while POLY(I:C) disrupts neuronal
calcium dynamics independent of iMG, ibuprofen rescues this effect only if iMG
are present. Mechanistically, ibuprofen targets the enzymes cyclooxygenase 1 and
2 (COX1/PTGS1 and COX2/PTGS2) simultaneously, from which iMG mainly express COX1.
Selective COX1 blockage fails to restore the calcium peak amplitude upon POLY(I:C)
stimulation, suggesting ibuprofen’s beneficial effect depends on the presence
and interplay of COX1 and COX2. These findings underscore the importance of microglia
in the context of prenatal immune challenges and provide insight into the mechanisms
by which ibuprofen exerts its protective effects during embryonic development.
acknowledged_ssus:
- _id: LifeSc
- _id: Bio
acknowledgement: We thank the scientific service units at ISTA, specifically the Lab
Support Facility (LSF), the Molecular Biology Services/Virus Services Team, specifically
Flavia Gama Gomes Leite and Mark Andrew Smyth, for the virus production, and the
Imaging and Optics Facility (IOF). We thank all members of the Siegert group and
Marco Benevento for their constant feedback on the project and comments on the manuscript.
A special thanks to Rouven Schulz for input on statistical analysis and sharing
R-scripts, Gloria Colombo for the introduction to cell sorting, Negar Vehdani and
Florianne Schoot Uiterkamp for their support in cell culture. This research was
supported by the Gesellschaft für Forschungsförderung Niederösterreich (grant No.
Sc19-017 to V.H.).
article_number: '98'
article_processing_charge: Yes
article_type: original
author:
- first_name: Verena
full_name: Hübschmann, Verena
id: 32B7C918-F248-11E8-B48F-1D18A9856A87
last_name: Hübschmann
- first_name: Medina
full_name: Korkut, Medina
id: 4B51CE74-F248-11E8-B48F-1D18A9856A87
last_name: Korkut
orcid: 0000-0003-4309-2251
- first_name: Alessandro
full_name: Venturino, Alessandro
id: 41CB84B2-F248-11E8-B48F-1D18A9856A87
last_name: Venturino
orcid: 0000-0003-2356-9403
- first_name: Juan Pablo
full_name: Maya-Arteaga, Juan Pablo
id: c815d433-1f5d-11f0-a875-dad18b1e5924
last_name: Maya-Arteaga
- first_name: Sandra
full_name: Siegert, Sandra
id: 36ACD32E-F248-11E8-B48F-1D18A9856A87
last_name: Siegert
orcid: 0000-0001-8635-0877
citation:
ama: Hübschmann V, Korkut M, Venturino A, Maya-Arteaga JP, Siegert S. Microglia
determine an immune-challenged environment and facilitate ibuprofen action in
human retinal organoids. Journal of Neuroinflammation. 2025;22(1). doi:10.1186/s12974-025-03366-x
apa: Hübschmann, V., Korkut, M., Venturino, A., Maya-Arteaga, J. P., & Siegert,
S. (2025). Microglia determine an immune-challenged environment and facilitate
ibuprofen action in human retinal organoids. Journal of Neuroinflammation.
Springer Nature. https://doi.org/10.1186/s12974-025-03366-x
chicago: Hübschmann, Verena, Medina Korkut, Alessandro Venturino, Juan Pablo Maya-Arteaga,
and Sandra Siegert. “Microglia Determine an Immune-Challenged Environment and
Facilitate Ibuprofen Action in Human Retinal Organoids.” Journal of Neuroinflammation.
Springer Nature, 2025. https://doi.org/10.1186/s12974-025-03366-x.
ieee: V. Hübschmann, M. Korkut, A. Venturino, J. P. Maya-Arteaga, and S. Siegert,
“Microglia determine an immune-challenged environment and facilitate ibuprofen
action in human retinal organoids,” Journal of Neuroinflammation, vol.
22, no. 1. Springer Nature, 2025.
ista: Hübschmann V, Korkut M, Venturino A, Maya-Arteaga JP, Siegert S. 2025. Microglia
determine an immune-challenged environment and facilitate ibuprofen action in
human retinal organoids. Journal of Neuroinflammation. 22(1), 98.
mla: Hübschmann, Verena, et al. “Microglia Determine an Immune-Challenged Environment
and Facilitate Ibuprofen Action in Human Retinal Organoids.” Journal of Neuroinflammation,
vol. 22, no. 1, 98, Springer Nature, 2025, doi:10.1186/s12974-025-03366-x.
short: V. Hübschmann, M. Korkut, A. Venturino, J.P. Maya-Arteaga, S. Siegert, Journal
of Neuroinflammation 22 (2025).
corr_author: '1'
date_created: 2025-04-20T22:01:28Z
date_published: 2025-04-03T00:00:00Z
date_updated: 2025-09-30T12:17:04Z
day: '03'
ddc:
- '570'
department:
- _id: SaSi
doi: 10.1186/s12974-025-03366-x
external_id:
isi:
- '001459311800002'
pmid:
- '40181459'
file:
- access_level: open_access
checksum: dcc355c21ab713e45fda5c61b5fa5299
content_type: application/pdf
creator: dernst
date_created: 2025-04-22T09:46:27Z
date_updated: 2025-04-22T09:46:27Z
file_id: '19607'
file_name: 2025_JourNeuroinflammation_Schmied.pdf
file_size: 4482167
relation: main_file
success: 1
file_date_updated: 2025-04-22T09:46:27Z
has_accepted_license: '1'
intvolume: ' 22'
isi: 1
issue: '1'
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 9B99D380-BA93-11EA-9121-9846C619BF3A
grant_number: SC19-017
name: How human microglia shape developing neurons during health and inflammation
publication: Journal of Neuroinflammation
publication_identifier:
eissn:
- 1742-2094
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
record:
- id: '20074'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Microglia determine an immune-challenged environment and facilitate ibuprofen
action in human retinal organoids
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 22
year: '2025'
...