2. Academic Validation
  3. Mitogen-activated protein kinase phosphatase-1 controls PD-L1 expression by regulating type I interferon during systemic Escherichia coli infection

Mitogen-activated protein kinase phosphatase-1 controls PD-L1 expression by regulating type I interferon during systemic Escherichia coli infection

  • J Biol Chem. 2022 May;298(5):101938. doi: 10.1016/j.jbc.2022.101938.
Timothy J Barley 1,  Parker R Murphy 1,  Xiantao Wang 2,  Bridget A Bowman 1,  Justin M Mormol 1,  Carli E Mager 1,  Sean G Kirk 1,  Charles J Cash 1,  Sarah C Linn 3,  Xiaomei Meng 1,  Leif D Nelin 4,  Bernadette Chen 4,  Markus Hafner 2,  Jian Zhang 5,  Yusen Liu 6
Affiliations

Affiliations

  • 1 Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 2 Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, Maryland, USA.
  • 3 Combined Anatomic Pathology Residency/Graduate Program, Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA; Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 4 Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
  • 5 Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
  • 6 Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA. Electronic address: yusen.liu@nationwidechildrens.org.
PMID: 35429501 DOI: 10.1016/j.jbc.2022.101938
Abstract

Mitogen-activated protein kinase Phosphatase 1 (Mkp-1) KO mice produce elevated cytokines and exhibit increased mortality and Bacterial burden following systemic Escherichia coli Infection. To understand how Mkp-1 affects immune defense, we analyzed the RNA-Seq datasets previously generated from control and E. coli-infected Mkp-1+/+ and Mkp-1-/- mice. We found that E. coli Infection markedly induced programmed death-ligand 1 (PD-L1) expression and that Mkp-1 deficiency further amplified PD-L1 expression. Administration of a PD-L1-neutralizing monoclonal antibody (mAb) to Mkp-1-/- mice increased the mortality of the Animals following E. coli Infection, although Bacterial burden was decreased. In addition, the PD-L1-neutralizing mAb increased serum interferon (IFN)-γ and tumor necrosis factor alpha, as well as lung- and liver-inducible nitric oxide synthase levels, suggesting an enhanced inflammatory response. Interestingly, neutralization of IFN-α/β receptor 1 blocked PD-L1 induction in Mkp-1-/- mice following E. coli Infection. PD-L1 was potently induced in macrophages by E. coli and lipopolysaccharide in vitro, and Mkp-1 deficiency exacerbated PD-L1 induction with little effect on the half-life of PD-L1 mRNA. In contrast, inhibitors of Janus kinase 1/2 and tyrosine kinase 2, as well as the IFN-α/β receptor 1-neutralizing mAb, markedly attenuated PD-L1 induction. These results suggest that the beneficial effect of type I IFNs in E. coli-infected Mkp-1-/- mice is, at least in part, mediated by Janus kinase/signal transducer and activator of transcription-driven PD-L1 induction. Our studies also support the notion that enhanced PD-L1 expression contributes to the bactericidal defect of Mkp-1-/- mice.

Keywords

infection; inflammation; interferon; phosphatase; sepsis.

Figures
Products