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Toll-Like Receptor 2–Mediated Autophagy Promotes Microglial Cell Death by Modulating the Microglial M1/M2 Phenotype

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Abstract

Toll-like receptor 2 (TLR2) regulates the innate immune response of microglia during infection via autophagy. Microglial M1/M2 phenotypic switching after infection could serve as a novel pathogenic mechanism for cerebral infection. Hence, it has important implications for the damage and restoration of neurological function. However, the effect of TLR2-mediated autophagic signaling on microglial phenotypic transition remains unclear. Therefore, we investigated the mechanisms of TLR2-mediated autophagic signaling in the regulation of microglial M1/M2 phenotypes. Using Western blot analysis and immunofluorescence, increased autophagy was observed in peptidoglycan (PGN)-stimulated BV2 cells, while reduced autophagy was observed in TLR2-KO cells. In contrast to the TLR2 antagonist CU-CPT22 group, increased autophagy was observed in the presence of the TLR2 agonist Pam3CSK4, which was associated with a significant increase in expression levels of M1 phenotype biomarkers (CD86, TNF-α, IL-6), higher levels of apoptosis, and decreased expression levels of M2 markers (CD206, IL-10, Arg-1). In the TLR2-KO mice, the expression levels of autophagy-related proteins in CD11b+ cells were lower than those in CD11b+ cells in the PGN-injected wild-type mice, and neuronal apoptosis was also reduced, but there were no significant differences compared to the control group. Collectively, our study demonstrates that the inhibition of autophagy or the absence of TLR2 induces microglial polarization towards the M2 phenotype, promotes microglial survival alone, and alleviates the development of neuroinflammation. In summary, TLR2-mediated autophagic signaling contributes to regulating the inflammatory response to activate microglial M1/M2 switching, which affects microglial survival after infection.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation (Project no. 31571557).

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Authors and Affiliations

  1. Department of Pediatrics, Qilu Hospital, Shandong University, No. 107, Wen Hua Xi Road, Jinan, 250012, Shandong, China

    Kun Ma, Guan Wang & Xinjie Liu

  2. The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China

    Kun Ma & Qiuying Ni

  3. Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

    Jingjing Guo

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  1. Kun Ma
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Contributions

Xinjie Liu: study conception and design; Kun Ma: experiments and manuscript writing; Jingjing Guo: data collection and analysis; Guan Wang and Qiuying Ni: material preparation and data collection

All authors read and approved the final manuscript.

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Correspondence to Xinjie Liu.

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The authors declare that they have no conflict of interest.

Ethical Approval

The experiments complied with the Regulations of the Administration of Laboratory Animals of the Ministry of Health of China (Document No. 55 of 2001) and were approved by the Animal Ethics Committee of Shandong University, China.

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Main Points

• Transition from the M1 to the M2 phenotype promotes microglial survival.

• Autophagy is associated with the M1 phenotype and increased apoptosis.

• Inhibition or absence of TLR2 is associated with reduced autophagy.

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Ma, K., Guo, J., Wang, G. et al. Toll-Like Receptor 2–Mediated Autophagy Promotes Microglial Cell Death by Modulating the Microglial M1/M2 Phenotype. Inflammation 43, 701–711 (2020). https://doi.org/10.1007/s10753-019-01152-5

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  • DOI: https://doi.org/10.1007/s10753-019-01152-5

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