ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion

Clinical and Translational Medicine, 2024 · DOI: 10.1002/ctm2.1661 · Published: April 2, 2024

Simple Explanation

Spinal cord injury (SCI)-induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation-activated microglia after SCI. Here, we identified an unreported ACOD1-p62-Nrf2-ACOD1 feedback loop exerting anti-inflammatory and anti-OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita.

Study Duration

Not specified

Participants

Adult male C57BL/6 ACOD1−/− mice and their wild-type (WT) littermates

Evidence Level

Not specified

Key Findings

1
ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury.
2
ACOD1, not itaconate, interacted with p-p62 to facilitate Nrf2 expression and nuclear translocation.
3
Nrf2 was capable of promoting ACOD1 transcription in microglia.

Research Summary

Here, we identified an unreported ACOD1-p62-Nrf2-ACOD1 feedback loop exerting anti-inflammatory and anti-OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita. Taken together, we identified a new positive feedback loop inhibiting inflammation and OS, where ACOD1 promotes p62 phosphorylation at Ser351 and further depolymerises the Keap1–Nrf2 complex.

Practical Implications

Neuroprotective Target

ACOD1 is a key early target regulating neuroinflammation and OS after SCI.

Unique Regulatory Role

ACOD1 may positively regulate autophagy in a manner different from that of exogenous Ita.

Therapeutic Potential

Future studies are needed to explain the difference between endogenous ACOD1/Ita and exogenous Ita and its derivatives.

Study Limitations

1
High ACOD1/Nrf2 expression in SCI mice (3 h post-SCI) showed shorter time than that in vitro debris-treated microglia (24 h post-debris treatment), which may be attributed to the complicated microenvironment and intercellular regulatory mechanisms.
2
The current study focused on the mechanism of how ACOD1/Nrf2 regulates microglia-induced neuroinflammation, but it is unclear what the role of ACOD1 and exogenous Ita are in autophagy.
3
Not specified

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