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

Content Provider	Europe PMC
Author	Barley, Timothy J. Murphy, Parker R. Wang, Xiantao Bowman, Bridget A. Mormol, Justin M. Mager, Carli E. Kirk, Sean G. Cash, Charles J. Linn, Sarah C. Meng, Xiaomei Nelin, Leif D. Chen, Bernadette Hafner, Markus Zhang, Jian Liu, Yusen
Copyright Year	2022
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.
ISSN	00219258
Volume Number	298
PubMed Central reference number	PMC9108994
Issue Number	5
PubMed reference number	35429501
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2022.101938
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2022-04-13
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2022 The Authors
Subject Keyword	infection phosphatase sepsis interferon inflammation Ab, antibody ASGR1, asialoglycoprotein receptor 1 BMDM, bone marrow–derived macrophage CLP, cecal ligation and puncture IFN, interferon IFNAR1, IFN-α/β receptor 1 IL, interleukin iNOS, inducible nitric oxide synthase IRF, IFN regulatory factor JAK, Janus kinase LPS, lipopolysaccharide mAb, monoclonal antibody MFI, mean fluorescent intensity Mkp, mitogen-activated protein kinase phosphatase NO, nitric oxide PD-1, programmed death-1 PD-L1, programmed death-ligand 1 PE, phycoerythrin qRT–PCR, quantitative RT–PCR STAT, signal transducer and activator of transcription TNF-α, tumor necrosis factor alpha TYK2, tyrosine kinase 2
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry