Year-end Sale % OFF 
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. The mortality of HLH is higher in the elderly than in young adults. Senescence-accelerated mice (SAMP1/TA-1) exhibit characteristic accelerated aging after 30 weeks of age, and HLH-like features, including hematopoietic organ damage, are seen after lipopolysaccharide (LPS) treatment. Thus, SAMP1/TA-1 is a useful model of hematological pathophysiology in the elderly with HLH. In this study, dosing of SAMP1/TA-1 mice with LPS revealed that the suppression of myelopoiesis and B-lymphopoiesis was more severe in aged mice than in young mice. The bone marrow (BM) expression of genes encoding positive regulators of myelopoiesis (G-CSF, GM-CSF, and IL-6) and of those encoding negative regulators of B cell lymphopoiesis (TNF-α) increased in both groups, while the expression of genes encoding positive-regulators of B cell lymphopoiesis (IL-7, SDF-1, and SCF) decreased. The expression of the GM-CSF-encoding transcript was lower in aged mice than in young animals. The production of GM-CSF by cultured stromal cells after LPS treatment was also lower in aged mice than in young mice. The accumulation of the TNF-α-encoding transcript and the depletion of the IL-7-encoding transcript were prolonged in aged mice compared to young animals. LPS dosing led to a prolonged increase in the proportion of BM M1 macrophages in aged mice compared to young animals. The expression of the gene encoding p16INK4a and the proportion of β-galactosidase- and phosphorylated ribosomal protein S6-positive cells were increased in cultured stromal cells from aged mice compared to those from young animals, while the proportion of Ki67-positive cells was decreased in stromal cells from aged mice. Thus, age-related deterioration of stromal cells probably causes the suppression of hematopoiesis in aged mice. This age-related latent organ dysfunction may be exacerbated in elderly people with HLH, resulting in poor prognosis.
Highlights
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder
It has been reported that the prognosis of patients with secondary HLH (sHLH) is poorer in the elderly than in young adults, little is known about the pathogenesis and the pathophysiology that lead to worse prognoses among elderly patients with sHLH10,12–14
The numbers of peripheral white blood cells (WBCs), red blood cells (RBCs), and platelets were evaluated in the blood of young and aged SAMP1/TA-1 mice nine days after dosing with saline or LPS (Fig. 1)
Summary
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. Age-related deterioration of stromal cells probably causes the suppression of hematopoiesis in aged mice This age-related latent organ dysfunction may be exacerbated in elderly people with HLH, resulting in poor prognosis. We recently found that SAMP1/TA-1 mice dosed repeatedly with lipopolysaccharide (LPS) exhibit HLH-like features such as severe pancytopenia, hepatomegaly, splenomegaly, hypofibrinogenemia, hyperferritinemia, and hemophagocytosis in peripheral blood, BM, and spleen; they serve as a useful model of sHLH20. The mRNA levels of positive regulators of B lymphopoiesis, such as IL-7, stromal-cell derived factor-1 (SDF-1), and stem cell factor (SCF) are profoundly decreased in both the BM and cultured stromal c ells[21] Senescence markers, such as the expression of the gene encoding p16INK4a and the proportion of β-galactosidase-positive cells, are increased in cultured stromal c ells[21]. We chose the hematopoietic organ to investigate differences in the pathophysiology of sHLH between young and elderly adults
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
