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Heightened turnover and failed maturation of monocyte-derived macrophages in Chronic Granulomatous Disease

ABSTRACT: Loss of NADPH oxidase activity in phagocytes leads to altered cellular responses and exaggerated inflammation in Chronic Granulomatous Disease (CGD). We sought to assess the effects of Nox2 absence on monocyte-derived macrophages (MoMacs) in gp91phox-/y mice during zymosan-induced peritonitis. MoMacs from CGD and wild type (WT) peritonea were lavaged and characterized over time. Though the numbers harvested from both genotypes were virtually identical, there were marked differences in maturation: newly recruited WT MoMacs rapidly enlarged and matured with loss of Ly6C and gain of MHCII, CD206 and CD36, while MoMacs in CGD remained small and were mostly Ly6C+MHCII-. RNAseq analyses showed few intrinsic differences between genotypes in newly recruited MoMacs, but significant differences over time. WT MoMacs demonstrated changes in metabolism, adhesion and reparative functions, while CGD MoMacs remained inflammatory. Labeling with PKH dye demonstrated that while WT MoMacs were mostly recruited within the first 24 hours and remained in the peritoneum while maturing and enlarging, CGD monocytes continued to stream into the peritoneum for days with many migrating to the diaphragm where they were found in fibrin(ogen) clots surrounding clusters of neutrophils in what appeared to be nascent granulomata. Importantly, these observations appeared to be entirely driven by the milieu: adoptive transfer of CGD MoMacs into inflamed peritonea of WT mice resulted in immunophenotypic maturation and behavior, and conversely, altered maturation/behavior of WT MoMacs was seen after adoptive transfer into inflamed peritonea of CGD mice. These data demonstrate heightened recruitment and fundamental failure of MoMac maturation in CGD.

ORGANISM(S): Mus musculus

PROVIDER: GSE166542 | GEO | 2024/02/10

REPOSITORIES: GEO

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Project description:Background and aims: Gene mutations or variants leading to insufficient reactive oxygen species (ROS) production have been associated with inflammatory bowel disease (IBD). In particular, 40-50% of patients with chronic granulomatous disease have IBD (CGD-IBD). CGD is caused by inherited defects in any one of the 5 subunits forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived ROS production. While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection in this immune compromised population. Understanding the impact of NOX2 defects on the composition and function of the intestinal microbiota may lead to the identification of treatments for CGD-IBD. Methods: We evaluated GI symptom and quality of life scores, and clinical biomarkers of local (i.e. fecal occult blood and calprotectin) and systemic (i.e. CBC, CRP, ESR, and albumin) inflammation in a cohort of 79 patients with CGD, 8 mutation carriers and 17 healthy controls followed at the National Institutes of Health (NIH). We profiled the intestinal microbiome by 16S rRNA (V4 region) sequencing and the stool metabolome by mass spectrometry in all fecal samples, and further validated our findings by profiling the stool microbiome in a second cohort of 36 patients with CGD recruited from 11 centers across North-America through the Primary Immune Deficiency Treatment Consortium (PIDTC). Predictive functional profiling of the microbial communities based on 16S rRNA sequencing was also performed. Results: After controlling for significant variables, we show decreased alpha diversity and identified distinct intestinal microbiome and metabolomic profiles in patients with CGD compared to healthy individuals. In particular, we observed enrichment for Erysipelatoclostridium spp., Sellimonas spp. and Lachnoclostridium spp. in stool samples from patients with CGD. Despite differences in alpha and beta diversity in samples from the NIH compared to the PIDTC cohort, there were several bacterial taxa that correlated significantly between both cohorts. We further demonstrate that patients with active IBD and/or a history of IBD have a distinct microbiome and metabolomic profile compared to patients without CGD-IBD and identified bacterial taxa to be evaluated as potential markers of disease severity, as well as targets for future therapeutic interventions. Conclusions: Intestinal microbiome and metabolomic signatures distinguished patients with CGD and CGD-IBD and identified microbial and metabolomic candidates to be further evaluated as potential targets to improve the management of patients with CGD-IBD.

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Heightened turnover and failed maturation of monocyte-derived macrophages in Chronic Granulomatous Disease

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