Interleukin-22 (IL-22) Binding Protein Constrains IL-22 Activity, Host Defense, and Oxidative Phosphorylation Genes during Pneumococcal Pneumonia

Infect Immun. 2019 Oct 18;87(11):e00550-19. doi: 10.1128/IAI.00550-19. Print 2019 Nov.

Abstract

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by Il22ra2 To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner. Il22ra2-/- mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected Il22ra2-/- mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from Il22ra2-/- mice displayed reduced OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that Il22ra2-/- macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.

Keywords: IL-22BP; OXPHOS; host defense.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Disease Susceptibility
  • Epithelial Cells / physiology
  • Gene Expression Regulation
  • Interleukin-22
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Leukocyte Common Antigens
  • Lung / cytology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Oxidation-Reduction
  • Phosphorylation
  • Pneumonia, Pneumococcal / immunology
  • Pneumonia, Pneumococcal / metabolism*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism*
  • Streptococcus pneumoniae

Substances

  • Interleukins
  • Receptors, Interleukin
  • interleukin-22 receptor
  • Leukocyte Common Antigens
  • Ptprc protein, mouse