Inhibition of PTP1B Promotes M2 Polarization via MicroRNA-26a/MKP1 Signaling Pathway in Murine Macrophages

Xiaolong Xu,Yuhong Guo,Yongming Yao,Shasha He,Marc Fisher,Qingquan Liu,Xuerui Wang,Ning Wang,Yan Lin,Yunjing Bai

doi:10.3389/fimmu.2019.01930

Abstract

Sepsis is a life-threatening condition that often occurs in the intensive care unit. The excessive activation of the host's immune system at early stages contributes to multiple organ damage. Mitogen-activated protein kinase phosphatase-1 (MKP1) exerts an important effect on the inflammatory process. In our recent bioinformatic analysis, we confirmed that the inhibition of protein tyrosine phosphatase-1B (PTP1B) significantly promoted the expression of MKP1 in murine macrophages. However, the underlying mechanism and its effect on macrophage polarization remain unclear. In this study, we show that the suppression of PTP1B induced upregulation of MKP1 in M1 macrophages. A RayBiotech mouse inflammation antibody assay further revealed that MKP1-knockdown promoted pro-inflammatory cytokine (IL-1β, IL12p70, IL-17, IL-21, IL-23, and TNF-α) secretion but suppressed anti-proinflammatory cytokine (IL-10) production in M2 macrophages. Phospho-proteomics analysis further identified ERK1/2 and p38 as downstream molecules of MKP1. Moreover, we found that the inhibition of PTP1B lowered the expression of miR-26a, showing a negative correlation with MKP1 protein expression. Thus, we concluded that the inhibition of PTP1B contributes to M2 macrophage polarization via reducing mir-26a and afterwards enhancing MKP1 expression in murine macrophages.

Highlights

Sepsis is a life-threatening condition seen in intensive care units (ICU) that is caused by a disordered reaction to infection [1, 2]
Our findings suggest that the prevention of the activity of protein tyrosine phosphatase-1B (PTP1B) decreases the production of miR-26a, which in turn enhances the expression of Mitogen-activated protein kinase phosphatase-1 (MKP1) and promotes M2 macrophage polarization
We characterized the role of PTP1B deficiency in promoting M2 macrophage polarization

Summary

Introduction

Sepsis is a life-threatening condition seen in intensive care units (ICU) that is caused by a disordered reaction to infection [1, 2]. Despite the development of supportive therapies, early treatment remains insufficient. The overall mortality of sepsis found in a recent cohort investigation involving 8,568 septic patients in the United States, was 15.7% [3]. A new definition of Sepsis-3.0 diminishes the significance of the systemic inflammatory response syndrome (SIRS), the mainstream view suggests that sepsis is caused by inappropriate regulation of the immune system [1]. A severe inflammatory response early after onset is essential for the excessive infiltration of inflammatory cells, leading to damage of tissue structure and dysfunction of organs [4].

Methods

Results

Conclusion