PP2ACα of Alveolar Macrophages Is a Novel Protective Factor for LPS-Induced Acute Respiratory Distress Syndrome

Abstract

Protein phosphatase 2A (PP2A) is one main serine/threonine phosphatase in eukaryotes, and its activation changes have been linked to modulation of numerous pathological processes, such as cancer, inflammation, fibrosis, and neurodegenerative diseases. Acute respiratory distress syndrome (ARDS), the major cause of respiratory failure, remains with limited therapies available up to now. Alveolar macrophages (AMs) are essential to innate immunity and host defense, participating in the pathogenesis of ARDS. As a result, AMs are considered as a potential therapeutic target for ARDS. In our study, we firstly found that PP2A activity was significantly decreased in the lipopolysaccharide (LPS)-stimulated AMs. Furthermore, adoptive transfer of AMs with enhanced PP2A enzyme activity that was improved by C2-ceramide prior to LPS exposure alleviated acute lung inflammation. Conversely, AM-specific ablation of PP2ACα exacerbated inflammatory responses to LPS. Mechanistically, PP2ACα negatively regulates LPS-induced cytokine secretion of AMs by NF-κB and MAPK pathways. Together, these findings provide the evidence to guide the development of novel therapeutic options targeting PP2ACα for ARDS/acute lung injury.

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Acknowledgements

We thank Dr. Xiang Gao (Nanjing University, Nanjing, China) for the PP2ACαf/f mice and Dr. Ximei-Wu (Zhejiang University, Hangzhou, China) for the LysMcre mice.

Funding

This work was supported by The National Natural Science Foundation of China 81700022 to Y.Z., The National Key Research and Development Plan 2018YFC1705500 to C.P., Research fund of Zhejiang Chinese Medical University 111100E013/001/001/029 and 111100E013/001/001/066 to Y.Z.

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H.Z., L.J., C.P., Y.K., and Y.Z. designed research; H.Z., L.J., and Y.Z. performed experiments, collected and analyzed data. H.Z. and Y.Z. wrote the paper; C.P. and Y.Z. critically revised the manuscript.

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Correspondence to Chengping Wen or Yun Zhang.

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He, Z., Du, L., Ke, Y. et al. PP2ACα of Alveolar Macrophages Is a Novel Protective Factor for LPS-Induced Acute Respiratory Distress Syndrome. Inflammation 42, 1004–1014 (2019). https://doi.org/10.1007/s10753-019-00962-x

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KEY WORDS

  • PP2ACα
  • Alveolar macrophages
  • C2-ceramide
  • Acute respiratory distress syndrome