Abstract
Attenuating the innate immunity activation could ameliorate inflammation and disease in settings such as transplant rejection or autoimmunity. Recently, a pivotal role for metabolic re-programming in TLR-induced dendritic cell (DC) activation has emerged. Ethyl pyruvate (EP), a pyruvate derivative, possesses anti-inflammatory properties in vitro and in animal models of disease. However, its effects on DCs remain elusive. We found that EP attenuated LPS-induced activation of murine GM-CSF bone marrow-derived dendritic cells (DCs) in vitro, reducing pro-inflammatory cytokine and IL-10 production, costimulatory molecule and MHC expression, the type I Interferon (IFN-I) response, the LPS-induced cell death, and the ability of DCs to stimulate allogeneic T cells. DC activation induced by TLR7 and TLR9 ligands was also suppressed by EP in vitro. Finally, EP decreased TLR-induced activation stimulated in vivo in conventional DCs and inflammatory monocytes. Investigating EP mechanisms, we found that EP decreased glycolysis and mitochondrial respiration, upon and in absence of TLR stimulation, by reducing ERK, AKT, and nitric oxide (NO) activation. These results indicate that EP inhibits most of the DC biological responses to TLR triggering, altering the metabolic reprogramming necessary for DC activation.
Highlights
GM-CSF-dendritic cells are an experimental model of inflammatory DCs [1], capable of sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), initiating the activation/maturation process [2,3,4,5]
We show that Ethyl pyruvate (EP) decreases DC immunometabolism by inhibiting the LPS-induced switch to glycolysis and decreasing mitochondrial respiration as well, without reducing DC survival
We found a dose-dependent decrease in IL-12p70 at 24 h (Figure 1F), and at 8, 48, and 72 h, starting with the lowest EP dose (1 mM) and reaching significance with the 3 highest doses
Summary
GM-CSF-dendritic cells (which we will refer to as DCs in this paper) are an experimental model of inflammatory DCs [1], capable of sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), initiating the activation/maturation process [2,3,4,5]. DCs up-regulate costimulatory molecules and secrete cytokines in order to present major histocompatibility complex (MHC)-restricted antigens to T lymphocytes in a pro-inflammatory context and induce an immune response. Pathological conditions, such as graft rejection, autoimmune diseases, and excessive inflammation warrant the dampening of dendritic cell activation to limit damaging immune responses. LPS stimulation has been shown to induce a metabolic reprogramming, which sustains GM-CSF-DC activation [6, 7] These DCs in a resting state support their energy needs through fatty acid oxidation to fuel the oxidative phosphorylation (OXPHOS) occurring in the mitochondria [7]. Around 24 h post-stimulation, glycolysis sustains DC survival, and the cells continue to function as Ag-Presenting Cells [12]
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