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

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.

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

“…In support of this notion, our EP transcriptome data showed that MF induced expression of signaling pathways of proinflammatory cytokines such as IL-15 and IL-22. These proinflammatory cytokines are produced mainly by inflammatory cells, including innate lymphocytes, T cells, and natural killer cells ( 26 , 27 ), and greatly contribute to the initiation and progression of inflammation status ( 27 – 29 ). Canonical pathway analysis showed that MF reduced the activity of the complement system in EP.…”

IL-22 Plays a Critical Role in Maintaining Epithelial Integrity During Pulmonary Infection

“…These data are consistent with a barrier protective role for IL-22 in the lung. The role of IL-22 has also been studied in the context of Streptococcus pneumoniae infection (12,13). IL-22-/-mice were shown to have increased bacterial burden in the lung compared to WT mice.…”

Stress-induced Differential Gene Expression in Cardiac Tissue

“…Among the differently expressed genes in the comparison of non-ICI treated rats, IL22RA2 (interleukin 22 receptor subunit alpha 2), IL2RA (interleukin 2 receptor antagonist) and IFRD1 (interferon related developmental regulator 1) were upregulated and are described as regulators of the in ammatory response [55,56]. IL-6, a pro-in ammatory cytokine produced by myeloid cells and cardiomyocytes in an autocrine mechanism [53], was also upregulated in this group.…”