10.3389/fimmu.2019.02236.s005 Virginia Meda Spaccamela Virginia Meda Spaccamela Rocio G. Valencia Rocio G. Valencia Oleksandr Pastukhov Oleksandr Pastukhov Andrea Duppenthaler Andrea Duppenthaler Matthias S. Dettmer Matthias S. Dettmer Juliane Erb Juliane Erb Urs C. Steiner Urs C. Steiner Sven Hillinger Sven Hillinger Carsten Speckmann Carsten Speckmann Stephan Ehl Stephan Ehl Janine Reichenbach Janine Reichenbach Ulrich Siler Ulrich Siler Image_3_High Levels of IL-18 and IFN-γ in Chronically Inflamed Tissue in Chronic Granulomatous Disease.JPEG Frontiers 2019 chronic granulomatous disease hyperinflammation macrophage priming macrophage re-priming IL-18/IFN-γ loop 2019-10-18 07:15:15 Figure https://frontiersin.figshare.com/articles/figure/Image_3_High_Levels_of_IL-18_and_IFN-_in_Chronically_Inflamed_Tissue_in_Chronic_Granulomatous_Disease_JPEG/10000520 <p>Background: Chronic granulomatous disease (CGD) is caused by a malfunctioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to impaired bacterial and fungal killing and hyperinflammation.</p><p>Objective: To characterize macrophage subsets and cytokine/chemokine signaling loops involved in CGD tissue hyperinflammation.</p><p>Methods: Cytokine/chemokine production and surface marker expression were analyzed in inflamed tissue of four CGD patients and compared to cytokine/chemokine released by CGD macrophages upon priming to different macrophage subpopulations. Furthermore, the re-priming capacity of CGD pro-inflammatory M1 to M2a anti-inflammatory macrophages was evaluated.</p><p>Results: In human CGD inflammatory tissue, IL-18 and IFN-γ were detected in significant quantity. Immunofluorescence analysis identified macrophages as one source of IL-18 in inflamed tissue. In vitro, CGD macrophages could be primed and re-primed into all inflammatory/anti-inflammatory macrophage subpopulations. IL-18 was also released by M1 CGD and control macrophages.</p><p>Conclusion: CGD pro-inflammatory M1 macrophages remain M1 primed in vivo. As CGD M1 macrophages can be re-primed to anti-inflammatory M2a phenotype in vitro, macrophages are kept in M1 state in vivo by a persistent pro-inflammatory environment. Our results suggest a paracrine signaling loop between M1 macrophage derived IL-18 and non-macrophage derived IFN-γ maintaining macrophage pro-inflammatory activity in CGD tissue.</p>