| First Author | Woo YD | Year | 2021 |
| Journal | J Allergy Clin Immunol | Volume | 147 |
| Issue | 4 | Pages | 1242-1260 |
| PubMed ID | 32910932 | Mgi Jnum | J:311040 |
| Mgi Id | MGI:6764861 | Doi | 10.1016/j.jaci.2020.07.038 |
| Citation | Woo YD, et al. (2021) Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine-tuning of GM-CSF receptor signaling. J Allergy Clin Immunol 147(4):1242-1260 |
| abstractText | BACKGROUND: Fine-tuning of immune receptor signaling is critical for the development and functioning of immune cells. Moreover, GM-CSF receptor (GM-CSFR) signaling plays an 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: Our aim was 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-CreSsu72(fl/fl) and Cd11c-CreSsu72(fl/fl) mice and used ovalbumin- or house dust mite-induced allergic asthma models. RESULTS: Following GM-CSF stimulation, Ssu72 directly bound to the GM-CSFR beta-chain in AMs, preventing phosphorylation. Consistently, mature Ssu72-deficient AMs showed higher phosphorylation of the GM-CSFR beta-chain and downstream molecules, which resulted in greater dysregulation of cell cycle, cell death, cell turnover, mitochondria-related metabolism, and LPS responsiveness in AMs than in mature wild-type AMs. The dysregulation was restored by using a Janus kinase 2 inhibitor, which reduced GM-CSFR beta-chain phosphorylation. LysM-CreSsu72(fl/fl) mice exhibited deficits in development and maturation of AMs, which were also seen postnatally in Cd11c-CreSsu72(fl/fl) mice. Furthermore, LysM-CreSsu72(fl/fl) mice were less responsive to ovalbumin- or house dust mite-induced allergic asthma models than the control mice were; however, their responsiveness was restored by adoptive transfer of JAK2 inhibitor-pretreated mature Ssu72-deficient AMs. CONCLUSION: Our results demonstrate that Ssu72 fine-tunes GM-CSFR signaling by both binding to and reducing phosphorylation of GM-CSFR beta-chain, thereby regulating the development, maturation, and mitochondrial functions of AMs and allergic airway inflammation. |
