Friday, July 4, 2014

Aryl hydrocarbon Receptor (AhR) keeps tissue "immune" memory alive

Lipopolysaccharide (LPS) is a part of gram-negative bacteria recognized by TLR4. Excessive activation of immune system by LPS induces sepsis. Earlier studies have shown that exposure to initial small doses of LPS renders the host more resilient (more tolerant) to subsequent exposure to higher doses of LPS. This effect is called LPS tolerance (a process more akin to biochemical adaptation).

The new study (1) published in Nature suggests that aryl hydrocarbon receptor activity controls LPS tolerance. AhR is host molecule that recognize endogenous products of tryptophan catabolism called kynurenines. Tryptophan catabolism in mammals is mediated by enzymes IDO1, IDO2 and TDO2 (this latter enzyme is mainly expressed in liver cells).

The authors examined the effect of primary LPS challenge on wild type, AhR-KO, IDO1-KO, IDO2-KO and TDO2-KO mice. Upon exposure to 10mg/kg of LPS, AhR-KO and TDO2-KO mice showed significantly higher level of mortality compared to wild-type or IDO2-KO mice. Of note, in these experiments, IDO2-KO mice behaved similar to wild-type mice (it appears that IDO2 plays no meaningful function in vivo) This increase in LPS sensitivity of AhR-KO and TDO2-KO mice was still observed when different doses of LPS was used (8-fold and 4-fold increase respectively). Interestingly, unlike at 2h post-exposure, levels of pro-inflammatory cytokines, IL-6, TNF-alpha and IL-1beta were higher in AhR-KO and TDO2-KO mice at 24h post-exposure compared to levels in wild-type mice. An opposite effect was seen with IL-10. AhR-KO and TDO2-KO mice expressed less IL-10 at 24h post LPS exposure.

These results indicated that activity of AhR or production of kynurenines had protective effect on host after primary LPS challenge. Indeed, LPS challenge of wild-type mice treated with TDO2 inhibitor dramatically reduced their survival that was reversed by exogenously administered L-kynurenine. This therapeutic effect of L-kynurenine was abolished in AhR-KO mice.

To examine the role of AhR in LPS tolerance, the authors re-exposed wild-type, IDO1-KO, IDO2-KO mice previously primed with primary dose of LPS. In this setting, only wild-type and IDO2-KO mice survived secondary LPS exposure, while IDO1-KO mice all died by day 10 post secondary LPS exposure. This resilience of wild-type mice to re-exposure to LPS was mediated by AhR activity since its blockade by specific inhibitor cut survival rate of pre-exposed wild-type mice. The authors showed that beneficial effect of AhR was mediated through TGF-beta and reduced expression of IL-6, TNF-alpha, not seen in IDO1-KO mice.

Finally, to see the effect of LPS tolerance in clinically relevant infection model, the authors infected mice with either gram-negative (S. Typhimurium) or gram-positive bacteria (group B Streptococcus). When mice were pre-exposed to LPS prior to infection with bacteria, they showed less immunopathology, reduced pro-inflammatory cytokine production and improved survival in response to infection compared to untreated control mice.

In summary, this study confirmed that the products of tryptophan catabolism activates AhR and contribute to increased tissue tolerance (biochemical adaptation) to secondary exposure to infection or noxious products. 


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