LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism

Abstract

Dendritic cells (DCs) are specialized antigen-presenting cells with a bipolar nature. Depending on environmental factors, DCs will promote either inflammatory or anti-inflammatory effects. Lipopolysaccharide (LPS), a ligand of Toll-like receptor (TLR)4 and a most potent proinflammatory stimulus, is responsible for complex signaling events in different cell types, including DCs. LPS effects range from protective inflammation-capable of counteracting growth and dissemination of gram-negative bacteria - to hyperacute detrimental responses, as it occurs in endotoxic shock. Consistent with the plasticity of TLR4 signaling, a low dosage of LPS will induce a regulatory response capable of protecting mice against a subsequent, otherwise lethal challenge ('endotoxin tolerance'). By examining CD11c(+) DCs ('conventional' DCs, or cDCs), we investigated whether DC flexibility in promoting either inflammation or tolerance can be differentially affected by single vs. repeated exposure to LPS in vitro. cDCs stimulated twice with LPS expressed high levels of indoleamine 2,3-dioxygenase 1 (IDO1) - one of the most effective mediator of anti-inflammatory activity by DCs - and of TGF-β, an immunoregulatory cytokine capable of upregulating IDO1 expression and function. In contrast, a single exposure to LPS failed to upregulate IDO1, and it was instead associated with high-level production of IL-6, a cytokine that promotes inflammation and proteolysis of IDO1. When adoptively transferred in vivo, only cDCs on double endotoxin exposure greatly improved the outcome of an otherwise lethal LPS challenge. The protective effect required that the transferred cDCs be fully competent for IDO1 and the host for TGF-β production. Thus cDCs, conditioned by LPS in vitro to mimic an endotoxin-tolerant state, can protect recipients from endotoxic shock, pointing to adoptive transfer of tolerance as a new option for controlling potentially harmful responses to TLR4 signaling.

Keywords: Adoptive transfer; Dendritic cells; Endotoxic shock; Endotoxin tolerance; IDO1; Tryptophan catabolism.