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The Long Non-coding RNA NEAT1/miR-224-5p/IL-33 Axis Modulates Macrophage M2a Polarization and A1 Astrocyte Activation

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Abstract

To identify potential regulators and investigate the molecular mechanism of macrophage polarization affecting astrocyte activation from the perspective of non-coding RNA regulation, we isolated mouse bone marrow mononuclear cells (BMMNCs)–induced macrophages toward M1 or M2a polarization. Long non-coding RNA NEAT1 and IL-33 expression levels were significantly upregulated in M2a macrophages; NEAT1 knockdown in M2a macrophages markedly reduced the protein levels of IL-33 and M2a markers, IL-4 and IL-13 concentrations, and the bacterial killing capacity of M2a macrophages. NEAT1 acted as a competing endogenous RNA (ceRNA) to regulate IL-33 expression by sponging miR-224-5p in M2a macrophages; NEAT1 knockdown upregulated miR-224-5p expression, while miR-224-5p inhibition increased the protein content and concentration of IL-33. miR-224-5p inhibition exerted the opposite effects on the protein levels of IL-33 and M2a markers, IL-4 and IL-13 concentrations, and the bacterial killing capacity of M2a macrophages compared to NEAT1 knockdown; the effects of NEAT1 knockdown were significantly reversed by miR-224-5p inhibition. M2a macrophage conditioned medium (CM) significantly suppressed the activation of A1 astrocytes. NEAT1 knockdown M2a macrophage CM led to enhanced A1 astrocyte activation while miR-224-5p–silenced M2a macrophage CM led to a blockade of A1 astrocyte activation; the effects of NEAT1 knockdown M2a macrophage CM on A1 astrocyte activation were significantly reversed by miR-224-5p inhibition in M2a macrophages. The NEAT1/miR-224-5p/IL-33 axis modulates macrophage M2a polarization, therefore affecting A1 astrocyte activation.

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Authors and Affiliations

  1. Department of Spine Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Dongliang Liu, Yudong Liu, Tianding Wu & Jianzhong Hu

  2. Department of Oncology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201900, China

    Yuehua Wei

  3. Research Centre of Sports Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Hongbin Lu

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Dongliang Liu, Jianzhong Hu, and Hongbin Lu made substantial contribution to the conception and design of the work. Tianding Wu and Yudong Liu analyzed and interpreted the data. Dongliang Liu and Yuehua Wei drafted the manuscript. Jianzhong Hu and Hongbin Lu revised the work critically for important intellectual content. Final approval of the work was made by all authors.

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Fig. S1

The differently expressed genes in GSE5296 (A), GSE42828 (B) and GSE93976 (C), ∣logfc∣ > 0.6, p < 0.05. (PNG 739 kb)

High Resolution Image (TIF 3158 kb)

Fig. S2

Expression of lncRNA NEAT1 after SCI or in macrophages based on online data. (A) GSE93976; (B) GSE42828; (C) GSE5296; (D) GSE71253; (E) GSE117040; (F) The expression correlation between IL-33 and NEAT1 based on GSE96054 and GSE93976. (PNG 256 kb)

High Resolution Image (TIF 257 kb)

Fig. S3

Inhibition of IL-33 reduced the expression of M2a markers in M2a macrophage. (A) M0 macrophages were transfected with si-IL33-1 and si-IL-33-2 and then induced M2a polarization. The expression of IL-33 in M2a macrophages was determined by immunoblotting. The si-IL-33-2 showed a better inference effect and was chosen for further experiments. (B) The levels of NEAT1 in si-IL-33 transfected M2a macrophages were determined by RT-PCR. (C-D) The M2a markers CD206, Arg-1, and YM-1, were determined by IF or western blot. **P < 0.05 compared to the si-NC group. (PNG 969 kb)

High Resolution Image (TIF 4565 kb)

Table S1

(DOCX 21 kb)

Supplementary File 1

The CT value of RT-PCR. (XLSX 44 kb)

Supplementary File 2

The raw data of PCR melting curve and amplification curve. (PDF 10520 kb)

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Liu, D., Wei, Y., Liu, Y. et al. The Long Non-coding RNA NEAT1/miR-224-5p/IL-33 Axis Modulates Macrophage M2a Polarization and A1 Astrocyte Activation. Mol Neurobiol 58, 4506–4519 (2021). https://doi.org/10.1007/s12035-021-02405-x

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