# Mkp-1 suppresses immune checkpoint protein PD-L1 to prevent sepsis-associated immune dysfunction and mortality

> **NIH NIH R21** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $190,000

## Abstract

Sepsis patients often develop cytokine storms in the early phase, and immunoparalysis associated with
lymphocyte apoptosis in the later phase of illness. The majority of sepsis-related deaths occur during this
secondary hypo-immune state, often due to a failure to clear pathogens. Recent studies have implicated
lymphopenia as an important component in the pathogenesis of sepsis-associated immunoparalysis. A
prospective cohort study found that monocyte programmed death-ligand 1 (PD-L1) expression was associated
with increased risk of mortality in septic patients. PD-L1 is an immune checkpoint protein. PD-L1 engagement
with programmed cell death protein 1 (PD-1), also an immune checkpoint protein, on T lymphocytes can lead
to lymphocyte apoptosis. Studies in animal models of sepsis have shown that blockade of PD-1 or PD-L1
attenuates lymphocyte apoptosis, alleviates organ damage, reduces bacterial burden, and decreases mortality.
Mkp-1 is a negative regulator of both p38 and JNK, and serves to restrain the production of both pro- and anti-
inflammatory cytokines (e.g., TNF-α, IL-6, and IL-10). In an E. coli-induced sepsis model, Mkp-1 knockout (KO)
mice exhibit features of severe sepsis, including substantially enhanced cytokine storm, exacerbated organ
damage, increased mortality, and elevated bacterial burden relative to wildtype (WT) mice. Septic Mkp-1 KO
mice also exhibited increased mortality relative to septic WT mice in a cecal ligation puncture model. Notably, a
clinic study has found that MKP-1 expression is suppressed in septic patients, highlighting the clinical
relevance of the Mkp-1 KO mouse model of sepsis. While studies in our laboratory and by others suggest that
excessive IL-6 and IL-10 in Mkp-1 KO mice are, at least partially, responsible for the compromised bacterial
clearance, the mechanisms remain unclear. Recently, we have found that PD-L1 expression in E. coli-infected
Mkp-1 KO mice is substantially higher than that in similarly infected WT mice. Moreover, PD-L1 expression is
tightly correlated with IL-6, IL-10, and STAT3 expression. While PD-L1 can be induced by IFNs via the
JAK/STAT pathway, type I & II IFN mRNA were barely detectable. Since IL-6 and IL-10 also regulate the
JAK/STAT pathway, we postulate that in the later stage of sepsis IL-6, IL-10, and perhaps also circulating IFNs
up-regulate PD-L1 expression via the JAK/STAT pathway. We further hypothesize that over-produced IL-6 and
IL-10 or IFNs in septic Mkp-1 KO mice compromise immune defense by potentiating lymphocyte apoptosis via
augmenting PD-L1 expression, ultimately increasing bacterial burden and mortality. In this proposal, we
propose two Aims to test these hypotheses. Aim 1 will assess whether PD-L1 neutralizing antibody decreases
bacterial burden and mortality in septic Mkp-1 KO mice. Aim 2 will assess whether IL-6 and IL-10 enhance PD-
L1 expression and if JAK inhibitors attenuate PD-L1 expression, decrease bacterial burden, and increase
animal survival i...

## Key facts

- **NIH application ID:** 9869859
- **Project number:** 5R21AI142885-02
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Yusen Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,000
- **Award type:** 5
- **Project period:** 2019-02-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869859

## Citation

> US National Institutes of Health, RePORTER application 9869859, Mkp-1 suppresses immune checkpoint protein PD-L1 to prevent sepsis-associated immune dysfunction and mortality (5R21AI142885-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9869859. Licensed CC0.

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