Aryl hydrocarbon receptor control of a disease tolerance defence pathway

Abstract

Summary Disease tolerance is the ability of the host to reduce the impact of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (“endotoxin tolerance”). We found that a first exposure to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase 2, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR complex-associated Src kinase activity promoted IDO1 phosphorylation and signaling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in gram-negative and gram-positive infections, pointing to a role for AhR in contributing to host fitness.

Disease tolerance and immunity in host protection against infection

“…This is not specific to TLR4, occurring downstream of other PRRs 125 and other sensors 18 . In some instances this response, coined as "trained immunity" 126 , has been functionally linked to the induction of disease tolerance 18 .…”

“…These cytokines include IL-1α, IL-18 and IL-33, which polarize macrophages towards tissue healing regenerative responses, and as discussed in the previous section, contribute to the establishment of disease tolerance to infection (Figure 3a). Signaling via the aryl hydrocarbon receptor (AhR) a ligand-dependent transcription factor that senses exogenous environmental toxins and endogenous ligands, can also polarize macrophages towards the establishment of disease tolerance to bacterial infections 18 .…”

“…Autophagy modulates disease tolerance to a variety of infections 63 64 17 . Signaling via these sensors, polarizes macrophage responses to assist parenchyma cells in restoring homeostasis 18,166,167 . This non cell-autonomous mechanism supporting tissue damage control and disease tolerance to infection is mediated via the secretion of cytokines, e.g.…”

“…This notion has been challenged over the past years by the (re)discovery of disease tolerance 5,6 . This evolutionarily conserved host defense strategy, which was first described in plants 7,8 , is fully operational in flies 9,10 and mammals, including rodents 11,12 and humans 13 , where it preserves host homeostasis in response to viral 14,15 , bacterial [15][16][17][18] , fungal 19 and protozoan 11,13,20,21 infections. In contrast to resistance to infection, disease tolerance does not exert a direct negative effect on these pathogens 6 .…”

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Results from a variety of laboratories over the past decade have revealed that the AHR has key roles in the development of cardiovascular, reproductive, and neural systems as well as in hematopoiesis and regulation of immune responses (Benedict, Lin, Loeffler, Peterson, & Flaws, 2000; Esser & Rannug, 2015; Gasiewicz, Singh, & Bennett, 2014; Kimura, Ding, & Tohyama, 2016; Lahvis et al., 2005; Quintana & Sherr, 2013; Singh et al., 2014; Stockinger, Di Meglio, Gialitakis, & Duarte, 2014). Some of these functions may involve natural or endogenous ligands such as metabolites generated by the microbiome, tryptophan metabolites, or lipid‐derived molecules (Bessede et al., 2014; Hubbard, Murray, & Perdew, 2015; McMillan & Bradfield, 2007; Moura‐Alves et al., 2014). The exact relationship between the AHR‐dependent toxicity of DLCs and PAHs and these physiological roles of AHR is not yet clear.…”