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FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression

Abstract

IL-10-producing B cells (B10) are involved in the prevention of autoimmune and allergic responses but its mechanisms remain poorly understood. We took advantage of the ovalbumin-induced asthma mouse model to demonstrate that the activity of FoxO1 is upregulated in lung B cells and correlates inversely with B10 cells, while showing decreased activity in ex vivo and in vitro induced B10 cells. We further observed that FoxO1 deficiency leads to increased frequency of B10 cells. These observations have in vivo clinical evidence, as B cell specific FoxO1 deficiency leads to reduced lung eosinophils and asthma remission in mice, and there are reduced regulatory B cells and increased FoxO1 activity in B cells of asthma patients. Single cell RNA-sequencing data demonstrated a negative correlation between the expression of Foxo1 and Il10 in B cells from the mouse spleen and lung and the human lung. For a biological mechanism, FoxO1 inhibits the expression of Prdm1, which encodes Blimp-1, a transcription factor of B10 cells. Our experimental evidence in both murine and human asthma demonstrates that FoxO1 is a negative regulator of B10 cell differentiation via negatively regulating Prdm1 and its expression in B cells contributes to allergic asthma disease.

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Fig. 1: Increased FoxO1 activity in B cells and decreased B10 cells in OVA-induced asthma model and asthma patients.
Fig. 2: B10 cells manifest decreased FoxO1 activity.
Fig. 3: Deletion of FoxO1 in B cells ameliorates asthma.
Fig. 4: BALF and lung cytology of CD19Cre/+ Foxo1fl/fl mice and control littermates after asthma induction.
Fig. 5: FoxO1 negatively regulates B10 cell differentiation by suppressing Prdm1 expression.
Fig. 6: Transfer of FoxO1 deficient B cells to WT mouse alleviates allergic asthma disease.

Data availability

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

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82120108013, 81801607, 81901652), the National Key R&D Program of China (2017YFA0205600), the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2017ZT07S054), and the Guangdong Basic and Applied Basic Research Foundation (2020A1515010897).

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Contributions

L.L. and Z.X.L. designed the experiments. S.R.W., R.D.H., M.M., X.Y., and L.L. performed the experiments and analyzed the data. M.M. analyzed the single cell RNA-sequencing data. S.R.W., M.M., L.L., Z.B.Z., C.S., M.E.G. and Z.X.L. wrote and edited the manuscript. H.Y.C. and Y.H. provided human samples, participated in experiment design and edited the manuscript. D.M.X. participated in experiment design and manuscript editing.

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Correspondence to Liang Li or Zhe-Xiong Lian.

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Wang, SR., Hu, RD., Ma, M. et al. FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression. Mucosal Immunol 15, 459–470 (2022). https://doi.org/10.1038/s41385-022-00504-z

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