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Background  In conditions of immunosuppression, the central nervous sty 5ystem (CNS) is the main target tissue for the reactivation of infection by  Trypanosoma cruzi , the causative agent of Chagas disease. In experimental  T. cruzi  infection, interferon gamma (IFNγ) +  microglial cells surround astrocytes harboring amastigote parasites. In vitro, IFNγ fuels astrocyte infection by  T. cruzi , and IFNγ-stimulated infected astrocytes are implicated as potential sources of tumor necrosis factor (TNF). Pro-inflammatory cytokines trigger behavioral alterations. In  T. cruzi -infected mice, administration of anti-TNF antibody hampers depressive-like behavior. Herein, we investigated the effects of TNF on astrocyte susceptibility to  T. cruzi  infection and the regulation of cytokine production.    Methods  Primary astrocyte cultures of neonatal C57BL/6 and C3H/He mice and the human U-87 MG astrocyte lineage were infected with the Colombian  T. cruzi  strain. Cytokine production, particularly TNF, and TNF receptor 1 (TNFR1/p55) expression were analyzed. Recombinant cytokines (rIFNγ and rTNF), the anti-TNF antibody infliximab, and the TNFR1 modulator pentoxifylline were used to assess the in vitro effects of TNF on astrocyte susceptibility to  T. cruzi  infection. To investigate the role of TNF on CNS colonization by  T. cruzi , infected mice were submitted to anti-TNF therapy.    Results  rTNF priming of mouse and human astrocytes enhanced parasite/astrocyte interaction (i.e., the percentage of astrocytes invaded by trypomastigote parasites and the number of intracellular parasite forms/astrocyte). Furthermore,  T. cruzi  infection drove astrocytes to a pro-inflammatory profile with TNF and interleukin-6 production, which was amplified by rTNF treatment. Adding rTNF prior to infection fueled parasite growth and trypomastigote egression, in parallel with increased TNFR1 expression. Importantly, pentoxifylline inhibited the TNF-induced increase in astrocyte susceptibility to  T. cruzi  invasion. In  T. cruzi -infected mice, anti-TNF therapy reduced the number of amastigote nests in the brain.    Conclusions  Our data implicate TNF as a promoter of  T. cruzi  invasion of mouse and human astrocytes. Moreover, the TNF-enriched inflammatory milieu and enhanced TNFR1 expression may favor TNF signaling, astrocyte colonization by  T. cruzi  and egression of trypomastigotes. Therefore, in  T. cruzi  infection, a self-sustaining TNF-induced inflammatory circuit may perpetuate the parasite cycle in the CNS and ultimately promote cytokine-driven behavioral alterations.    Electronic supplementary material  The online version of this article (doi:10.1186/s12974-017-0952-0) contains supplementary material, which is available to authorized users.

Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu