Enhanced Expression of Catalase in Mitochondria Modulates NF-κB–Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages

  • Han W
  • Fessel J
  • Sherrill T
  • et al.
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Abstract

NF-κB is a reduction-oxidation–sensitive transcription factor that plays a key role in regulating the immune response. In these studies, we intended to investigate the role of mitochondrial-derived reactive oxygen species in regulating NF-κB activation by studying transgenic mice that overexpress mitochondrial-targeted human catalase (mCAT). We treated wild-type (WT) and mCAT mice with intratracheal instillation of Escherichia coli LPS and found that mCAT mice had exaggerated NF-κB activation in the lungs, increased neutrophilic alveolitis, and greater lung inflammation/injury compared with WT mice. Additional studies using bone marrow chimeras revealed that this hyperinflammatory phenotype was mediated by immune/inflammatory cells. Mechanistic studies using bone marrow–derived macrophages (BMDMs) showed that LPS treatment induced a sustained increase in NF-κB activation and expression of NF-κB–dependent inflammatory mediators in mCAT BMDMs compared with WT BMDMs. Further investigations showed that cytoplasmic, but not mitochondrial, hydrogen peroxide levels were reduced in LPS-treated mCAT BMDMs. However, mCAT macrophages exhibited increased glycolytic and oxidative metabolism, coupled with increased ATP production and an increased intracellular NADH/NAD+ ratio compared with BMDMs from WT mice. Treatment of BMDMs with lactate increased the intracellular NADH/NAD+ ratio and upregulated NF-κB activation after LPS treatment, whereas treatment with a potent inhibitor of the mitochondrial pyruvate carrier (UK5099) decreased the NADH/NAD+ ratio and reduced NF-κB activation. Taken together, these findings point to an increased availability of reducing equivalents in the form of NADH as an important mechanism by which metabolic activity modulates inflammatory signaling through the NF-κB pathway.

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APA

Han, W., Fessel, J. P., Sherrill, T., Kocurek, E. G., Yull, F. E., & Blackwell, T. S. (2020). Enhanced Expression of Catalase in Mitochondria Modulates NF-κB–Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages. The Journal of Immunology, 205(4), 1125–1134. https://doi.org/10.4049/jimmunol.1900820

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