Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function

Abstract

SUMMARY Greater understanding of the complex host responses induced by type 1 Interferon (IFNs) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO, and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs.

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…In line with this discovery, TLR9 stimulation in pDCs led to an autocrine IFNAR signaling resulting in an increased fatty-acids oxidation and oxidative phosphorylation, which is key for pDC immune functions. 93 In addition, fasting or the administration of caloric restriction mimetics has been shown to improve the efficacy of immunogenic chemotherapy correlating with the depletion of immunosuppressive regulatory T (Treg) cells from the TME. 94 Notably, Type-I-IFNs are known to negatively regulate the proliferation and activity of Treg cells (panel 16, Fig.…”

Effects of Interferons and Viruses on Metabolism

“…Plasmacytoid dendritic cells (pDCs) are specialized immune cells devoted to the production of large amounts of type I IFNs after viral recognition (39). Mouse pDCs upregulate oxidative phosphorylation and ATP production 24 h after stimulation with poly(I:C) or directly after type I IFN treatment through an autocrine loop (40). This boost in energy production is required for full immune effector functions in vitro and for fighting lymphocytic choriomeningitis virus (LCMV) infection in vivo .…”

“…This boost in energy production is required for full immune effector functions in vitro and for fighting lymphocytic choriomeningitis virus (LCMV) infection in vivo . This increase in oxidative phosphorylation and mitochondrial respiration is fueled by FAO (40). Interestingly, the FAs required for FAO seem to be a result of de novo fatty acid synthesis (FAS) from glycolysis-derived pyruvate.…”

pDCs Take a Deep Breath to Fight Viruses

“…In this issue of Immunity, Wu et al (2016) addressed the question of whether changes in metabolism are also critical for pDC activation in response to TLR ligation. The authors begin by showing that CpGA (recognized via TLR9) and Imiquimod (a TLR7 agonist) induce an increase in pDC mitochondrial respiration, measured as the basal oxygen consumption rate (OCR).…”