Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Cell. 2019 May 16;177(5):1201-1216.e19. doi: 10.1016/j.cell.2019.03.018. Epub 2019 Apr 25.

Abstract

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Keywords: IL-23; UPR; dendritic cells; fatty acids; glycolysis; hexokinase; innate immunity; metabolic reprogramming; mtROS; psoriasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Microenvironment / genetics
  • Cellular Microenvironment / immunology*
  • Citric Acid Cycle / genetics
  • Citric Acid Cycle / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Hexokinase / genetics
  • Hexokinase / immunology
  • Immunity, Innate*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Reactive Oxygen Species / immunology*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / immunology*
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / immunology

Substances

  • Reactive Oxygen Species
  • Toll-Like Receptors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Hexokinase