Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines

To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites Trypanosoma cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen Leishmania mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. Trypanosoma cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. Keywords: Bone marrow macrophage response to intracellular parasites and cytokines We analyzed a series MEEBO arrays on which were hybed RNA amplified from bone marrow-derived macrophages from C57BL/6 mice. Macrophages infected with L. mexicana or T. cruzi or stimulated by LPS, IFNG, IL-4, IL-10, TNF, IFNB, or IL-17 were compared to one another as well as to uninfected, unstimulated control macrophages. All experiments were performed over a 24 h timecourse with timepoints taken at 2 h, 6 h, 12 h, and 24 h.