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Publication

Transcriptome analysis of monocytes and macrophages in mycobacterial infection and chronic kidney disease

Book - Dissertation

Tissue macrophages and their circulating counterpart, the monocytes, constitute a key component of the innate immune system. Different triggers evoke different macrophage responses leading to different states of macrophage activation. The activation states of the following in vivo elicited macrophages were characterized by transcriptome profiling: (i) granuloma macrophages from mice after infection with Mycobacterium bovis BCG, and (ii) monocytes from patients with chronic kidney disease. Granuloma macrophages constitute an important component of granulomas, which are cellular aggregates of T cells and activated macrophages, and which are hallmarks of tuberculosis. By genome-wide expression profiling, we identified a specific molecular marker SynCAM1 for Th1 cytokine-related granuloma macrophages within the mononuclear phagocyte family. Moreover, we identified the differential regulation in granuloma macrophages of genes not previously associated with the in vivo macrophage response during mycobacterial infection. These included several chemotaxis-related genes and adhesion molecules. The regulation of SynCAM1 and some of the other newly identified molecules was dependent on TNF-derived signals, indicating that TNF might contribute to granuloma formation and/or maintenance not only by regulating expression of chemokines, but also expression of adhesion molecules in the granuloma. Thus, we identified several valuable targets for future research that might improve our understanding of the involvement of macrophages and of TNF in the granulomatous response during mycobacterial infection. Another part of the study was dedicated to the evaluation of monocytes from patients with chronic kidney disease (CKD). Monocytes in CKD are dysfunctional, and their particular activation state is believed to contribute to the major complications observed in CKD: (i) the slight pro-inflammatory activation state might contribute to accelerated atherosclerosis in CKD, and (ii) the blunted immune response upon further stimulation might contribute to increased susceptibility to infections. The transcriptome of monocyte/macrophage-related genes was analyzed in monocytes from CKD patients and controls, however, hardly any differences in gene expression were observed in the different study populations. Our results, together with previously described observations, indicate that it is only the CD16+ monocyte subset that is affected in CKD, and that post-transcriptional processes might be involved in the dysfunctional activation state.
Publication year:2010
Accessibility:Closed