Glycolytic Metabolism Is Critical for the Innate Antibacterial Defense in Acute Streptococcus pneumoniae Otitis Media.

Fangmei Fan,Xinxin Zhang,Dingyi Li,Rongshuang Ai,Yiting Zhu,Yujuan He,Zhiqiang Ding,Yilin Dong,Qian He,Yurong Ma

doi:10.3389/fimmu.2021.624775

Fangmei Fan, Xinxin Zhang + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.624775

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Abstract

Objective Streptococcus pneumoniae (S.pn) is a common respiratory pathogen and a frequent cause of acute otitis media (AOM) in children. However, little is known about the immunometabolism during AOM. This study was to assess the presence of glucose metabolic reprogramming during AOM and its underlying mechanism affecting inflammatory response and middle ear injury.MethodsThe levels of glycolytic metabolism were evaluated by measuring the expression of glycolysis-related genes and the production of metabolites. HE stain, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and Western blot were performed to measure the effect of glucose metabolic reprogramming on inflammatory response, pneumococcal clearance, hypoxia-inducible factor 1 alpha (HIF-1α) expression and cytokine secretion during AOM, respectively.ResultsThe analysis of microarray revealed an increase of the expression of glycolysis-related genes during S.pn–induced AOM, which was verified by real-time PCR. Increased glycolysis promoted the production of IL-1β and TNF-α and facilitated the clearance of S.pn by enhancing phagocytosis and killing capability of neutrophils, but also aggravated the middle ear injury. Furthermore, these pathogenic effects could be reversed after glycolytic inhibitor 2DG treatment. Additionally, HIF-1α was observed to involve in glycolytic metabolism during AOM.Conclusion S.pn infection induced increased glycolysis conversion during AOM, which promoted inflammatory responses and bacterial clearance, but also aggravated tissue damage.

Highlights

Acute Otitis Media (AOM) is one of the most prevalent infectious diseases worldwide, especially in children [1]
The analysis of microarray revealed an increase of the expression of glycolysisrelated genes during S.pn–induced AOM, which was verified by real-time PCR
We examined the regulation of S.pn on the glycolytic metabolism of middle ear epithelial cells and neutrophils recruited into the middle ear, which represent non-immune cell types and innate immune cell types respectively

Summary

Introduction

Acute Otitis Media (AOM) is one of the most prevalent infectious diseases worldwide, especially in children [1]. Accumulating studies have found that tumor cells and activated immune cells, including macrophages, dendritic cells, Th17 cells and so on, have undergone “metabolic reprogramming” [5,6,7,8,9]. Neutrophils are the most predominant innate defenders against S.pn, which rapidly migrate to middle ear cavity upon infection [18, 19]. It is well known that the mucous epithelium of middle ear undergoes extensive modification of immune response during OM, including the recruitment of nonresident leukocyte species [20]. No study has investigated the features of metabolic changes of middle ear epithelial cells and neutrophils recruited to the middle ear cavity. Given that metabolic changes have proved essential for some key immune-regulatory events downstream of TLR activation, we hypothesized that metabolic reprogramming involved in the innate immune responses during AOM

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Conclusion