Human endogenous retrovirus W family envelope protein (HERV-W env) facilitates the production of TNF-α and IL-10 by inhibiting MyD88s in glial cells

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Abstract

Human endogenous retrovirus W family envelope protein (HERV-W env) is associated with several neurological and psychiatric disorders, including multiple sclerosis (MS) and schizophrenia. Clinical studies have demonstrated a common link between inflammatory abnormalities and HERV-W env in neuropsychiatric diseases. Nonetheless, the molecular mechanisms by which HERV-W env mediates neuroinflammation are still unclear. In this study, we found that HERV-W env significantly increased the mRNA and protein levels of TNF-α and IL-10 in U251 and A172 cells. HERV-W env also induced a notable increase in Toll-like receptor 4 (TLR4). Knockdown of TLR4 impaired the expressions of TNF-α and IL-10 induced by HERV-W env. Overexpression of HERV-W env led to the upregulation of MyD88 but caused a decrease in MyD88s. MyD88s overexpression suppressed the expressions of TNF-α and IL-10 induced by HERV-W env. These findings indicate that HERV-W env upregulates the expressions of IL-10 and TNF-α by inhibiting the production of MyD88s in glial cells. This work sheds light on the immune pathogenesis of HERV-W env in neuropsychiatric disorders.

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Change history

  • 20 January 2021

    ORCHID of author Fan ZHU corrected.

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Acknowledgements

This work was supported by grants from the National Natural Sciences Foundation of China (grant nos. 81971943, 81772196, 31470264, 81271820, 30870789, and 30300117) and the Stanley Foundation from the Stanley Medical Research Institute (SMRI), United States (grant no. 06R-1366) for Dr. F Zhu, and the Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (grant no. TFJC 2018002).

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Overexpression of HERV-W env in U251 and A172 cells. (A) Protein expression level of HERV-W env after overexpression of HERV-W env in U251 cells. (B) Protein expression level of HERV-W env after overexpression of HERV-W env in A172 cells (JPEG 124 kb)

Time-course analysis of TNF-α and IL-10 by ELISA in U251 and A172 cells. (A and B) Expression levels of TNF-α in the culture supernatant and lysates of U251 cells at 12, 24, 36, and 48 hours after transfection, measured by ELISA. (C and D) Expression levels of TNF-α in the culture supernatant and lysates of A172 cells at 12, 24, 36, and 48 hours after transfection, measured by ELISA. (E and F) Expression levels of IL-10 in the culture supernatant and lysates of U251 cells at 12, 24, 36, and 48 hours after transfection, measured by ELISA. (G and H) Expression levels of IL-10 in the culture supernatant and lysates of A172 cells at 12, 24, 36, and 48 hours after transfection, measured by ELISA (JPEG 770 kb)

Knockdown of TLR4 suppresses the expression of TNF-α and IL-10 in U251 and A172 cells. (A and B) Expression levels of TNF-α in lysates of U251 and A172 cells transfected with HERV-W env and siTLR4, measured by ELISA assay. (C and D) Expression levels of IL-10 in lysates of U251 and A172 cells transfected with HERV-W env and siTLR4, measured by ELISA. Data represent the mean ± standard deviation of three independent experiments. *, P < 0.05 compared to pCMV, pCMV-env, or pCMV-env + siTLR4 (JPEG 440 kb)

Overexpression of MyD88s in U251 and A172 cells. (A) Protein expression level of MyD88s after overexpression of MyD88s in U251 cells. (B) Protein expression level of MyD88s after overexpression of MyD88s in A172 cells (JPEG 112 kb)

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Wang, X., Wu, X., Huang, J. et al. Human endogenous retrovirus W family envelope protein (HERV-W env) facilitates the production of TNF-α and IL-10 by inhibiting MyD88s in glial cells. Arch Virol 166, 1035–1045 (2021). https://doi.org/10.1007/s00705-020-04933-8

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