Dynamic State of Cytoplasmic Deoxyguanosine Kinase Controls Classically Activated Macrophage Polarization Process

Macrophage-mediated inflammation has a significant bursting period and restoring period, which suggests the presence of intrinsic anti-inflammatory mechanisms. Here, we reported a dynamic regulator, cytoplasmic deoxyguanosine kinase (dGK), in the process of macrophage polarization and homeostasis. Firstly, we confirmed a positive correlation between dGK and the procedure of classically activated macrophages polarization. Moreover, dGK was proved to maintain STAT1 phosphorylation via binding the C-terminal domain of STAT1, which facilitated STAT1-Jak2 interaction and simultaneously blocked interaction with the phosphatase, TC45, during initial phase of proinflammatory macrophage polarization. However, in the inflammation resolution phase, macrophage suffered from increased autophagy which consequently restrained proinflammatory phenotype by inducing the degradation of dGK. Further we screened a variety of small molecules and found that PMFA ameliorated inflammation depending on autophagy-mediated dGK degradation. These findings revealed the dynamic regulation mode of dGK during classically activated macrophage polarization and the maintained immune homeostasis.