Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host-pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNγ (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb-induced differentially expressed genes revealed various terms, related to host-protection and inflammation, enriched in up-regulated genes. On the other hand, terms related to dis-regulation of cellular functions were enriched in down-regulated genes. Differential expression analysis revealed known as well as novel transcription factor genes in Mtb infection, many of them significantly down-regulated. IFNγ or IL-4/IL-13 pre-stimulation induce additional differentially expressed genes in Mtb-infected macrophages. Cluster analysis uncovered significant numbers, prolonging their expressional changes. Furthermore, Mtb infection augmented cytokine-mediated M1 and M2 pre-activations. In addition, we identified unique transcriptional features of Mtb-mediated differentially expressed lncRNAs. In summary we provide a comprehensive in depth gene expression/regulation profile in Mtb-infected macrophages, an important step forward for a better understanding of host-pathogen interaction dynamics in Mtb infection.

The role of proinflammatory cytokines in cognitive function has been investigated with both beneficial and possible detrimental effects, depending on the cytokine. More recently, the type 2 IL-4 has been demonstrated to play a role in cognition. In this study, using the Morris water maze task, we demonstrate that IL-13-deficient mice are significantly impaired in working memory as well as attenuated reference memory, both functions essential for effective complex learning. During the learning process, wild-type mice increased the number of CD4 T cells in the meninges and production of IL-13, whereas neither Morris water maze-trained IL-4 nor trained IL-13-deficient mice were able to increase CD4 T cells in the meninges. Mechanistically, we showed that IL-13 is able to stimulate primary astrocytes to produce brain-derived neurotrophic factor, which does foster cognitive functions. Moreover, Morris water maze-trained wild-type mice were able to increase astrocyte-produced glial fibrillary acidic protein in the hippocampus, which was impaired in Morris water maze-trained IL-4- and IL-13-deficient mice. Collectively, this study strongly suggests that the Th2 cytokines, not only IL-4 but also IL-13, are involved in cognitive functions by stimulating astrocytes from the meninges and hippocampus. These results may be important for future development of therapeutic approaches associated with neurologic disorders such as Parkinson disease-associated dementia and HIV-associated dementia among others.