Meda Spaccamela, VirginiaVirginiaMeda SpaccamelaValencia, Rocio GRocio GValenciaPastukhov, OleksandrOleksandrPastukhovDuppenthaler, AndreaAndreaDuppenthaler0000-0002-6861-8603Dettmer, MatthiasMatthiasDettmer0000-0003-0948-1392Erb, JulianeJulianeErbSteiner, Urs CUrs CSteinerHillinger, SvenSvenHillingerSpeckmann, CarstenCarstenSpeckmannEhl, StephanStephanEhlReichenbach, JanineJanineReichenbachSiler, UlrichUlrichSiler2024-10-282024-10-282019https://boris-portal.unibe.ch/handle/20.500.12422/183000Background: 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.enIL-18/IFN-γ loop chronic granulomatous disease hyperinflammation macrophage priming macrophage re-priming600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.7892/boris.1346293168125710.3389/fimmu.2019.02236