Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague-Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg-1 day-1 MNX (» LD50 ) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1+ -macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd.

Blockage of caspase-1 activation ameliorates bone marrow inflammation in mice after hematopoietic stem cell transplantation.

Conditioning regimens before hematopoietic stem cell transplantation (HSCT), cause damage to bone marrow and inflammation. Whether inflammasomes are involved in bone marrow inflammation remains unclear. The study aims to evaluate the role of inflammasomes in bone marrow inflammation after HSCT. On days 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of bone marrow inflammation, pro-inflammatory cytokines secretion, inflammasomes expression and caspase-1 activation. Bone marrow inflammation with neutrophils and macrophages infiltration was observed after HSCT. Secretion of IL-1ß, IL-18, TNF-α and IL-6 were elevated, with increased caspase-1 activation and inflammasomes expression. Caspase-1 inhibitor administration after HSCT significantly reduced infiltration of neutrophils and macrophages into bone marrow and increased the numbers of megakaryocytes and platelets. In conclusion, inflammasomes activation is involved in bone marrow inflammation after HSCT and caspase-1 inhibition attenuates bone marrow inflammation and promoted hematopoietic reconstitution, suggesting targeting caspase-1 might be beneficial for improving HSCT outcomes.

New evidence for dietary fatty acids in the neutrophil traffic between the bone marrow and the peripheral blood.

Chronic administration of a high-fat diet in mice has been established to influence the generation and trafficking of immune cells such as neutrophils in the bone marrow, the dysregulation of which may contribute to a wide range of diseases. However, no studies have tested the hypothesis that a short-term, high-fat diet could early modulate the neutrophil release from bone marrow at fasting and at postprandial in response to a high-fat meal challenge, and that the predominant type of fatty acids in dietary fats could play a role in both context conditions. Based on these premises, we aimed to establish the effects of different fats [butter, enriched in saturated fatty acids (SFAs), olive oil, enriched in monounsaturated fatty acids (MUFAs), and olive oil supplemented with eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] on neutrophil navigation from bone marrow to blood in mice. The analysis of cellular models for mechanistic understanding and of postprandial blood samples from healthy volunteers for translational purposes was assessed. The results revealed a powerful effect of dietary SFAs in promotion the neutrophil traffic from bone marrow to blood via the CXCL2-CXCR2 axis. Dietary SFAs, but not MUFAs or EPA and DHA, were also associated with increased neutrophil apoptosis and bone marrow inflammation. Similar dietary fatty-acid-induced postprandial neutrophilia was observed in otherwise healthy humans. Therefore, dietary MUFAs might preserve bone marrow health and proper migration of bone marrow neutrophils early in the course of high-fat diets even after the intake of high-fat meals.