IL-10 signaling modulates PRKN methylation and influences STAT3 activity to drive regulatory macrophage differentiation

The pathogenesis of many immune disorders is linked to regulatory macrophage dysfunction. The mechanism underlying it is unclear. The objective of this study is to examine the mechanism by which the PRKN ubiquitin protein ligase (PRKN) inhibits the development of regulatory macrophages (Mreg). In this study, dust mite antigens were used as the specific allergens to establish an airway allergy (AA) mouse model. Flow cytometry cell sorting was used to isolate macrophages from the airway tissues. According to the results, the Prkn gene inhibition led to an increase in the number of Mregs in macrophages. Mregs demonstrated the capacity to suppress Th2 polarization, in which IL-10 played a critical role. Pan macrophages isolated from Prkn-deficient mice were more capable of suppressing the activities of other immune cells. PRKN was required for maintaining the hyperubiquitous status of signal transducer and transcriptional activator-3 (STAT3) in macrophages. Exposure to dust mite antigen increased the expression of PRKN in macrophages. IL-10 suppressed PRKN in macrophages by inducing its promoter hypermethylation. PRKN inhibition mitigated the experimental AA. To sum up, PRKN maintains the hyper ubiquitous status of STAT3 and restricts the expression of IL-10 in macrophages, which compromises their immune suppressive functions. Inhibition of PRKN increases Mreg development and mitigates AA. The data suggest that the regulation of Mreg has translation potential to be used in the treatment of immune disorders such as AA.