한빛사 논문
Yeon Duk Woo PhD2, Jaemoon Koh MD, PhD1, Jae Sung Ko BS2, Sehui Kim MD1, Kyeong Cheon Jung MD, PhD1, Yoon Kyung Jeon MD, PhD1, Hye Young Kim PhD2, Ho Lee PhD3, Chang Woo Lee PhD4, Doo Hyun Chung MD, PhD1,2,*
1Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
2Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
3Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang 10408, Korea
4Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
*Corresponding author
Abstract
Background
Fine-tuning of immune receptor signaling is critical for the development and functioning of immune cells. Moreover, Granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) signaling plays essential role in the development of certain myeloid lineage cells including alveolar macrophages (AMs). However, the significance of fine-tuning of GM-CSFR signaling in AMs and its relevance in allergic inflammation have not been reported.
Objective
To explore whether phosphatase Ssu72, originally identified as a regulator of RNA polymerase II activity, regulates AM development and allergic airway inflammation by regulating GM-CSF signaling.
Methods
To address these issues, we generated LysM-CreSsu72fl/fl and Cd11c-CreSsu72fl/fl mice and ovalbumin (OVA)- or house dust mite (HDM)-induced allergic asthma models were used.
Results
Upon GM-CSF stimulation, Ssu72 directly bound to the GM-CSFR β chain (βc) in AMs, preventing phosphorylation. Consistently, mature Ssu72-deficient AMs showed higher phosphorylation of the GM-CSFR βc and downstream molecules, which resulted in greater dysregulation of cell cycle, cell death, cell turnover, mitochondria-related metabolism, and lipopolysaccharides (LPS) responsiveness in AMs compared to those of mature wild-type AMs. The dysregulation was restored using a Janus kinase (JAK)2 inhibitor, which reduced GM-CSFR βc phosphorylation. LysM-CreSsu72fl/fl mice exhibited deficits in the development and maturation of AMs, which were also seen postnatally in Cd11c-CreSsu72fl/fl mice. Furthermore, LysM-CreSsu72fl/fl mice was less responsive to OVA or HDM-induced allergic asthma models compared with control mice, which was restored by the adoptive transfer of JAK2 inhibitor-pretreated mature Ssu72-deficient AMs.
Conclusion
Our results demonstrate that Ssu72 finely tunes GM-CSFR signaling by both binding to and reducing the phosphorylation of GM-CSFR βc, thereby regulating the development, maturation and mitochondrial functions of AMs, and allergic airway inflammation.
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