Abstract
Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba−/− mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb−/− and Ncf1−/− models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba−/− mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.
Highlights
Our results show that granuloma inflammation lesions dramatically change haematopoiesis homeostasis
We have recently described the generation of a Cyba−/− mouse model using CRISPR/
We found a significant upregulation of the gene-encoding leukotriene B4 (LTB4) receptor (Ltb4r1 or BLT1) in the spleen of granuloma-bearing Cyba−/− mice (Figure 3E), suggesting that LTB4-BLT1 signalling could be contributing to inflammation and myelopoiesis in this organ
Summary
Chronic granulomatous disease (CGD) is the most common inherited disorder affecting the innate immune system [1,2]. CGD is caused by defects in the phagocyte oxidase, a membrane-bound complex that produces huge amounts of reactive oxygen species (ROS). During the respiratory burst, which is required for pathogen clearing [3]. Bacterial and fungal infections affecting airways, skin, gastrointestinal tract, lymph nodes, liver, brain, and bones can be life-threatening for CGD patients [2,4]. The severity of the disease varies among patients, and it seems that residual oxidase activity appears to improve patient survival [5]. Most patients develop symptoms early and are diagnosed during the first
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