Transporters MRP1 and MRP2 regulate opposing inflammatory signals to control transepithelial neutrophil migration during Streptococcus pneumoniae lung infection

Andrew Zukauskas, Randall J. Mrsny, Paula Cortés Barrantes, Jerrold R. Turner, John M. Leong, Beth A. McCormick

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection with S. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity. IMPORTANCE Streptococcus pneumoniae is a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid in S. pneumoniae elimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.

Original languageEnglish
Article numbere00303-18
Pages (from-to)1-15
Number of pages15
JournalmSphere
Volume3
Issue number4
DOIs
Publication statusPublished - 5 Jul 2018

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Transendothelial and Transepithelial Migration
Pneumococcal Infections
Neutrophils
Bacteremia
Lung
Neutrophil Infiltration
Infection
Biotinylation
ATP-Binding Cassette Transporters
Eicosanoids
Streptococcus pneumoniae
Meningitis
Developed Countries
Cell Movement
Pneumonia
Homeostasis
Anti-Inflammatory Agents
Epithelium
Morbidity
Mortality

Keywords

  • Hepoxilin A3
  • MRP1
  • MRP2
  • Neutrophil
  • PMN
  • Pneumococcus
  • Streptococcus pneumoniae
  • Cell Line
  • Humans
  • Epithelial Cells/enzymology
  • 8,11,14-Eicosatrienoic Acid/analogs & derivatives
  • Pneumonia, Pneumococcal/pathology
  • Respiratory Mucosa/enzymology
  • Neutrophils/immunology
  • Animals
  • Lung/pathology
  • Multidrug Resistance-Associated Proteins/metabolism
  • Mice
  • Cell Movement
  • Disease Models, Animal

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology

Cite this

Transporters MRP1 and MRP2 regulate opposing inflammatory signals to control transepithelial neutrophil migration during Streptococcus pneumoniae lung infection. / Zukauskas, Andrew; Mrsny, Randall J.; Barrantes, Paula Cortés; Turner, Jerrold R.; Leong, John M.; McCormick, Beth A.

In: mSphere, Vol. 3, No. 4, e00303-18, 05.07.2018, p. 1-15.

Research output: Contribution to journalArticle

Zukauskas, Andrew ; Mrsny, Randall J. ; Barrantes, Paula Cortés ; Turner, Jerrold R. ; Leong, John M. ; McCormick, Beth A. / Transporters MRP1 and MRP2 regulate opposing inflammatory signals to control transepithelial neutrophil migration during Streptococcus pneumoniae lung infection. In: mSphere. 2018 ; Vol. 3, No. 4. pp. 1-15.
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T1 - Transporters MRP1 and MRP2 regulate opposing inflammatory signals to control transepithelial neutrophil migration during Streptococcus pneumoniae lung infection

AU - Zukauskas, Andrew

AU - Mrsny, Randall J.

AU - Barrantes, Paula Cortés

AU - Turner, Jerrold R.

AU - Leong, John M.

AU - McCormick, Beth A.

N1 - Copyright © 2018 Zukauskas et al.

PY - 2018/7/5

Y1 - 2018/7/5

N2 - Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection with S. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity. IMPORTANCE Streptococcus pneumoniae is a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid in S. pneumoniae elimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.

AB - Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection with S. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity. IMPORTANCE Streptococcus pneumoniae is a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid in S. pneumoniae elimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.

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KW - Epithelial Cells/enzymology

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KW - Pneumonia, Pneumococcal/pathology

KW - Respiratory Mucosa/enzymology

KW - Neutrophils/immunology

KW - Animals

KW - Lung/pathology

KW - Multidrug Resistance-Associated Proteins/metabolism

KW - Mice

KW - Cell Movement

KW - Disease Models, Animal

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