A new study published in Brain Behavior and Immunity has suggested that acyl-CoA synthetase long-chain family member 4 (ACSL4) may be a novel regulator in promoting microglia-mediated neuroinflammation through regulation of vestigial-like family member 4 (VGLL4) expression and lipid metabolism.

The study found increased ACSL4 expression after the lipopolysaccharide (LPS) stimulation. Moreover, the knocking down of ACSL4 in microglia reduced the production of proinflammatory cytokines along with the alleviated neuroinflammation. Recent studies have shown that ACSL4 also affects the inflammatory response by modulating highly unsaturated fatty acids in bone marrow-derived macrophages and myeloid cells, the researchers noted.

Moreover, ACSL4 has been found to facilitate the production of inflammatory cytokines after ischemia, the study group said. However, it is not yet clear whether ACSL4 affects the inflammatory response in microglia after LPS stimulation and how it affects the progression of Parkinson’s disease, the investigators noted.

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The research team anesthetized male C57BL/6 mice weighing 20 to 22 grams and immobilized them in a stereotaxic apparatus. For knocking down the ACSL4, the team selected the shRNA sequence: GAGGCTTCCTATCTGATTA to construct the lentiviral vector. A number of antibodies were used in the experiments, including ACSL4, β-actin, antityrosine hydroxylase, GFAP, LPS, MPTP, Iba-1, Phospho-NF-κB p65, rabbit mAb, SAPK/JNK antibody, and laminA/C mouse antibody, the study team noted.

Study results of quantitative real-time PCR showed that the expression of ACSL4 mRNA was significantly increased after the LPS stimulation for 2 h, along with the increase in the protein level of ACSL4 after stimulation with LPS.

Moreover, compared to the siNC-transfected controls, the LPS-induced phosphorylation of NF-kB subunit P65 was considerably decreased in the BV2 microglia after the knockdown of ACSL4, the authors noted.

The flow cytometry results revealed that RSL3 treatment was not fruitful in increasing the protein expression of inflammatory cytokines being reduced in ACSL4-silenced microglia after the LPS stimulation for 4 h, indicating that the decreased proinflammatory cytokines production in ACSL4-silenced microglia did not result from the ferroptosis rate reduction.

“In conclusion, we reveal a novel role for ACSL4 in promoting microglia-mediated neuroinflammation by regulating VGLL4 expression and lipid metabolism,” the study team highlighted.

Neuroinflammation refers to the inflammation of nervous tissues and is triggered by various internal and external stimuli, including neuronal injury, toxic compounds, and invading pathogens. Microglia, the immune cells present in the central nervous system, play a significant role in initiating neuroinflammation in physiological and pathological conditions.


Zhou X, Zhao R, Lv M, et al. ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression. Brain, Behavior, and Immunity, Published online March 12, 2023.doi:10.1016/j.bbi.2023.02.012