AhR Controls Endotoxin Tolerance Pathway
Michael Denison, Ph.D.
University of California, Davis
NIEHS Grant R01ES007685
An NIEHS grantee and colleagues report new details regarding the mechanisms involved in endotoxin tolerance, a phenomenon in which prior exposure to endotoxin from Gram-negative bacteria reduces the host's inflammatory response to subsequent exposure. The findings could lead to new approaches for treating infectious diseases by controlling host-pathogen interactions.
Although endotoxin-induced inflammation is necessary for fighting Gram-negative bacteria, too much inflammation can cause damage and lead to sepsis. Endotoxin tolerance helps reduce over-exuberant inflammation, but its underlying mechanisms are not well understood. The researchers used genetically modified mice to investigate the biological pathways involved in endotoxin tolerance. They found that primary exposure of mice to LPS activated the aryl hydrocarbon receptor (AhR) transcription factor and the liver enzyme tryptophan 2,3-dioxygenase (TDO). However, when the mice were again exposed to LPS, AhR engaged in long-term regulation of systemic inflammation only when indoleamine 2,3-dioxygenase 1 (IDO1) was present. The resulting endotoxin tolerance protected the mice against immune response damage to both Gram-negative and Gram-positive infections.
The AhR receptor is also known to regulate toxic and biological effects of exogenous chemicals, and these new results point to a role for the receptor in contributing to host fitness.
Citation: Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML, Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, Nakamura T, Gilot D, Denison MS, Guillemin GJ, DuHadaway JB, Prendergast GC, Metz R, Geffard M, Boon L, Pirro M, Iorio A, Veyret B, Romani L, Grohmann U, Fallarino F, Puccetti P. 2014. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511(7508):184-190.
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