Knockout of MAPK Phosphatase-1 Exaggerates Type I IFN Response during Systemic Escherichia coli Infection

Abstract

Key Points Knockout of Mkp-1 exacerbates cytokine storms during E. coli–induced sepsis. Mkp-1 restrains IFN-β expression in macrophages by controlling p38 activity. Blocking type I IFN signaling during E. coli infection exacerbates disease severity. We have previously shown that Mkp-1–deficient mice produce elevated TNF-α, IL-6, and IL-10 following systemic Escherichia coli infection, and they exhibited increased mortality, elevated bacterial burden, and profound metabolic alterations. To understand the function of Mkp-1 during bacterial infection, we performed RNA-sequencing analysis to compare the global gene expression between E. coli–infected wild-type and Mkp-1−/− mice. A large number of IFN-stimulated genes were more robustly expressed in E. coli–infected Mkp-1−/− mice than in wild-type mice. Multiplex analysis of the serum cytokine levels revealed profound increases in IFN-β, IFN-γ, TNF-α, IL-1α and β, IL-6, IL-10, IL-17A, IL-27, and GMSF levels in E. coli–infected Mkp-1−/− mice relative to wild-type mice. Administration of a neutralizing Ab against the receptor for type I IFN to Mkp-1−/− mice prior to E. coli infection augmented mortality and disease severity. Mkp-1−/− bone marrow–derived macrophages (BMDM) produced higher levels of IFN-β mRNA and protein than did wild-type BMDM upon treatment with LPS, E. coli, polyinosinic:polycytidylic acid, and herring sperm DNA. Augmented IFN-β induction in Mkp-1−/− BMDM was blocked by a p38 inhibitor but not by an JNK inhibitor. Enhanced Mkp-1 expression abolished IFN-β induction by both LPS and E. coli but had little effect on the IFN-β promoter activity in LPS-stimulated RAW264.7 cells. Mkp-1 deficiency did not have an overt effect on IRF3/7 phosphorylation or IKK activation but modestly enhanced IFN-β mRNA stability in LPS-stimulated BMDM. Our results suggest that Mkp-1 regulates IFN-β production primarily through a p38-mediated mechanism and that IFN-β plays a beneficial role in E. coli–induced sepsis.