Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice

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.

Clinical and Hematologic Effects of Endotoxin in Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome Model Mice

“…LPS is known to induce leukopenia in WT C57BL/6 mice (13,14). To study whether this also occurs in WHIM mice on this genetic background, we challenged WHIM and WT littermates with a nonlethal 5 mg/kg dose of LPS and 3 h later analyzed blood leukocytes by flow cytometry.…”

“…Thus, CXCL12/CXCR4 signaling is critical for B lymphopoiesis and accounts for severe B lymphocytopenia in WHIM syndrome, yet LPS appears to anomalously abrogate this signal in a variant WHIM receptor-specific and pre-B cellspecific manner. Inflammation is known to downregulate CXCL12 in the bone marrow, but this should have a general effect of reducing retention of cells in the bone marrow (14,24,36). In addition to directly binding to and blocking CXCR4, AMD3100 has been reported to induce downregulation of CXCL12 in the bone marrow (37,38); however, there are no studies addressing the effect of LPS on this.…”

“…Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal-dominant, primary immunodeficiency disease caused by mutations that truncate the C-terminal tail of the chemokine receptor CXCR4 (14). WHIM mutations are predominantly CXCR4 protein-terminating nonsense mutations, although frameshifted missense mutations that add neosequence to the truncated natural C-tail also occur.…”

“…LPS is a major cell wall component of Gram-negative bacteria, which is recognized by the pattern recognition receptor TLR4 and is widely used to induce endotoxic shock in mice (12). Moreover, although bacterial sepsis and LPS challenge both rapidly induce severe lymphopenia (13,14), how leukocytes might redistribute during endotoxic shock in WHIM syndrome is not known.…”

Imbalanced M1 and M2 Macrophage Polarization in Bone Marrow Provokes Impairment of the Hematopoietic Microenvironment in a Mouse Model of Hemophagocytic Lymphohistiocytosis

“…Next, to detect inducible nitric oxide synthase (iNOS) and CD206, an Intracellular Fixation and Permeabilization Buffer Set (Catalog number: 88-8824; Thermo Fisher Scientific, Rockford, IL, U.S.A.) was used according to the manufacturer's instructions. 21) The washed cells were fixed by adding 100 µL of Fixation Buffer, and incubated for 30 min at room temperature in the dark. Then, 2 mL of Permeabilization Buffer was added, and the cells were centrifuged at 500 × g for 5 min at room temperature.…”