Ssu72 regulates alveolar macrophage development and allergic airway inflammation by fine tuning of GM-CSF receptor signaling.

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.