Search

Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression. [Display omitted] • Macrophage NCF1 contributes to impaired self-renewal of KCs and development of MASH • Macrophage NCF1 promotes oxidized phospholipids, which induce hepatocyte hepcidin • TLR4-dependent hepcidin production in hepatocytes promotes iron deposition in KCs • The human NCF1 low-functional variant alleviates KC iron deposition and MASH in mice Zhang et al. report that macrophage NCF1 oxidizes phospholipids, activating TLR4-dependent hepcidin production in hepatocytes. This, in turn, promotes iron deposition and ferroptosis in KCs, leading to a vicious loop and MASH progression. This highlights macrophage NCF1 as a promising therapeutic target for improving KC fate and MASH disease. [ABSTRACT FROM AUTHOR]

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22phox, p47phox, p67phox, and p40phox of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91phox leads to X-linked recessive CGD. Objective: The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. Methods: We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. Results: Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A220, A670 or X910 phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47phox-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index ? 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. Conclusion: Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A220 and A670 subtypes manifests as severe as the X910 subtype. [Copyright &y& Elsevier]