NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain
- 1Department of Anatomy, Inha University College of Medicine, Incheon, Republic of Korea
- 2Corresponding author.
Abstract
Peptidylarginine deiminase (PAD) catalyzes the post-translational conversion of positively charged arginine residues into neutral citrulline. This modification, known as citrullination, is implicated in various pathological conditions, including those affecting the central nervous system. This study investigated the pro-inflammatory role of PAD in microglia using a middle cerebral artery occlusion (MCAO) animal model of ischemic stroke. Pharmacological inhibition of PAD via BB-Cl-amidine (BBCA; a pan-PAD inhibitor) exerted robust anti-inflammatory and neuroprotective effects in the post-ischemic brain in a broad therapeutic window. A significant accumulation of citrullinated proteins was detected in activated microglia following ischemia, which was suppressed by BBCA. Notably, we demonstrate that citrullination of NEMO (IKKγ), a key regulator that activates the NF-κB signaling pathway, was significantly induced in the post-ischemic brain, facilitating NEMO-IKKα/IKKβ assembly. Importantly, BBCA inhibited NEMO citrullination and disrupted subsequent IKK assembly, highlighting the critical role of PAD in this process. Targeted knockdown experiments using siRNA in BV2 microglial cells revealed that both PAD2 and PAD4 play crucial role in NEMO citrullination and NF-κB-mediated pro-inflammatory response. Furthermore, inhibiting NEMO citrullination with a NEMO-binding domain peptide (NBDp) or co-treatment with NBDp and BBCA, further supports a crucial role for PAD-mediated NEMO citrullination in post-ischemic neuroinflammation. Collectively, these results suggest that PAD2 and PAD4 drive pro-inflammatory processes following cerebral ischemia by upregulating NEMO citrullination and subsequent IKK complex formation.
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BibTeX
@article{oh2026nemo,
title = {{NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain}},
author = {Sang-A Oh and Song-I Seol and Ja-Kyeong Lee and Il-Doo Kim},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01082},
url = {https://doi.org/10.1016/j.neurot.2026.e01082},
note = {CC BY},
}
RIS
TY - JOUR
TI - NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain
AU - Sang-A Oh
AU - Song-I Seol
AU - Ja-Kyeong Lee
AU - Il-Doo Kim
PY - 2026
DA - 2026/10/24
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01082
UR - https://doi.org/10.1016/j.neurot.2026.e01082
AB - Peptidylarginine deiminase (PAD) catalyzes the post-translational conversion of positively charged arginine residues into neutral citrulline. This modification, known as citrullination, is implicated in various pathological conditions, including those affecting the central nervous system. This study investigated the pro-inflammatory role of PAD in microglia using a middle cerebral artery occlusion (MCAO) animal model of ischemic stroke. Pharmacological inhibition of PAD via BB-Cl-amidine (BBCA; a pan-PAD inhibitor) exerted robust anti-inflammatory and neuroprotective effects in the post-ischemic brain in a broad therapeutic window. A significant accumulation of citrullinated proteins was detected in activated microglia following ischemia, which was suppressed by BBCA. Notably, we demonstrate that citrullination of NEMO (IKKγ), a key regulator that activates the NF-κB signaling pathway, was significantly induced in the post-ischemic brain, facilitating NEMO-IKKα/IKKβ assembly. Importantly, BBCA inhibited NEMO citrullination and disrupted subsequent IKK assembly, highlighting the critical role of PAD in this process. Targeted knockdown experiments using siRNA in BV2 microglial cells revealed that both PAD2 and PAD4 play crucial role in NEMO citrullination and NF-κB-mediated pro-inflammatory response. Furthermore, inhibiting NEMO citrullination with a NEMO-binding domain peptide (NBDp) or co-treatment with NBDp and BBCA, further supports a crucial role for PAD-mediated NEMO citrullination in post-ischemic neuroinflammation. Collectively, these results suggest that PAD2 and PAD4 drive pro-inflammatory processes following cerebral ischemia by upregulating NEMO citrullination and subsequent IKK complex formation.
SN - 1878-7479
SN - 1933-7213
ER -