AUTHOR=Meda Spaccamela Virginia , Valencia Rocio G. , Pastukhov Oleksandr , Duppenthaler Andrea , Dettmer Matthias S. , Erb Juliane , Steiner Urs C. , Hillinger Sven , Speckmann Carsten , Ehl Stephan , Reichenbach Janine , Siler Ulrich
TITLE=High Levels of IL-18 and IFN-γ in Chronically Inflamed Tissue in Chronic Granulomatous Disease
JOURNAL=Frontiers in Immunology
VOLUME=10
YEAR=2019
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02236
DOI=10.3389/fimmu.2019.02236
ISSN=1664-3224
ABSTRACT=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.
Objective: To characterize macrophage subsets and cytokine/chemokine signaling loops involved in CGD tissue hyperinflammation.
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.
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.
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.