The high levels of ISG15 induced locally in the FGT in response to Ct infection in WT mice, the exacerbated pathology and lower IL-10 levels observed in the FGT of infected ISG15−/− mice, and the evidence that ISG15 not only promotes an M2-like phenotype in macrophages but also counteracts the enhanced inflammatory response of polarized M1 macrophages in vitro, support the critical role of ISG15 in regulating inflammatory responses during chlamydial infection. Here, ISG15 is linked to infection.