O receptor aril hidrocarboneto como sensor da resposta imune inata: da influência no valor adaptativo do Trypanosoma cruzi ao controle da inflamação por células dendríticas na encefalomielite autoimune experimental.

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection, and in the context of autoimmune diseases as Multiple Sclerosis (MS) and its experimental model the experimental autoimmune encephalomyelitis (EAE). The relevance of AHR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild type (WT) and AHR KO mice with T. cruzi-Y strain and we quantified the levels of: parasitemia, myocardial inflammation and fibrosis, expression of AHR, cytokines, production of cytotoxic molecules in heart and/or spleen. AHR expression was increased in the heart of infected WT mice at 15 days post infection (dpi). Infected AHR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an increased immune response characterized by increased levels of inflammatory cytokines in the heart of these mice. In vitro, AHR deficiency caused impairment in parasite replication and decreased levels of ROS production and the expression control of key inflammation-physiological regulators. In the context of autoimmunity, AHR controls the efficacy of laquinimode (Laqui), a compound which is in stage III phase for the treatment of MS. Laquinimode have a suppressor effect on dendritic cells (DCs), thus is still not known if it is in an AHR -dependent manner. In BMDCs we did not observe a laquinimod-suppressor effect, but in DCs from spleen, we saw that laquinimod and delaquinimod (a laquinimod metabolite), were able to activate AHR and impair the inflammatory response in an AHR -dependent manner. Furthermore, we note adelaquinimod suppressor effect in the production of IL-6 and consequent reduction of IL-17 production by Th17 cells, and an increase in Treg cells, also in an AHR-DCs dependent manner. Herein, we demonstrated the anti-inflammatory role of AHR during experimental T. cruzi infectioin as well as during EAE, and the relevance of this receptor for the inate immune response