Aryl hydrocarbon receptor ligands enhance lung immunity through intestinal IKK\u03b2 pathways

Tzyy-Bin Tsay,Lee-Wei Chen,Pei-Hsuan Chen

doi:10.1186/s12967-019-2043-8

Abstract

BackgroundInfection by antibiotic-resistant microorganisms is common in intensive care units and has become a global problem. Here, we determined the effect of aryl hydrocarbon receptor (AhR) stimulation on antibiotics-induced systemic defense impairment and its mechanisms.MethodsC57BL/6 wild-type (WT) mice received combined antibiotics with or without Ahr ligands (tryptophan and indole), or dead Lactobacillus plantarum supplementation. The defense mechanisms against Pseudomonas aeruginosa infection in the lung were examined.ResultsAntibiotic treatments decreased the phagocytic activity, physiological activity, and the peroxynitrite production of alveolar macrophage (AMs). It also enhanced P. aeruginosa pneumonia-induced bacterial counts in the lung. Tryptophan and dead L. plantarum supplementation reversed antibiotic-induced intracellular adhesion molecule (ICAM) as well as IL-6 expression, and increased P. aeruginosa pneumonia-induced bacterial counts in the lung and increased phagocytic activity and peroxynitrite production of AMs. Moreover, these treatments reversed the antibiotics-induced reduction of Ahr expression, antibacterial proteins, reactive oxygen species (ROS) production, and NF-κB DNA binding activity of the intestinal mucosa and plasma IL-6 levels. P. aeruginosa counts increased and phagocytic activity of AMs and myeloperoxidase (MPO) activity decreased in intestinal IKKβ depleted mice. Antibiotics, antibiotic with tryptophan feeding, or antibiotic with dead L. plantarum feeding treatments did not change the phagocytic activity and peroxynitrite production of AMs, plasma IL-6 levels, and the expression of Ahr of intestine in intestinal IKKβ depleted mice.ConclusionAntibiotic treatment impairs lung immune defenses by decreasing Ahr expression in the intestine and peroyxnitrite production of the AMs. Ahr ligands reverses antibiotic-induced lung defense against bacterial infection through intestinal ROS production and NF-κB activation. The gut is critical in maintaining lung defense mechanism through the intestinal IKKβ pathways.

Highlights

Infection by antibiotic-resistant microorganisms is common in intensive care units and has become a global problem
Oral supplementation with Trp, or dead L. plantaris decreases P. aeruginosa pneumonia‐induced bacterial counts in the lung under antibiotic treatment To define the effects of antibiotic treatment on lung immune defenses against P. aeruginosa infection, we examined the bacterial counts from the lung in WT mice receiving P. aeruginosa intra-tracheal injection
Oral supplementation with Trp, or dead L. plantaris decreases P. aeruginosa pneumonia‐induced intracellular adhesion molecule (ICAM) and IL‐6 expression in the lung under antibiotic treatment In order to evaluate the effect of antibiotic treatment on Pseudomonas aeruginosa (PA)-induced lung inflammation, we assessed the ICAM and IL-6 mRNA expression in the lung tissue in WT mice

Summary

Introduction

Infection by antibiotic-resistant microorganisms is common in intensive care units and has become a global problem. We determined the effect of aryl hydrocarbon receptor (AhR) stimulation on antibioticsinduced systemic defense impairment and its mechanisms. The antibiotic-resistant infections that are difficult to treat are becoming more and more common. The intestinal epithelial cells express pattern recognition receptors that protect against antagonistic microbial invasion and maintain epithelial barriers in the presence of commensal microflora [6]. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor that is best known for mediating the carcinogenicity xenobiotic ligands. The regulatory mechanisms of the gut-lung axis and the role of the Ahr receptors of the intestinal mucosa in innate lung immunity have remained elusive

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