Spleen

Summary

The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . The spleen plays very important roles in regard to red blood cells (erythrocytes) and the immune system. It removes old red blood cells and holds a reserve of blood, which can be valuable in case of hemorrhagic shock, and also recycles iron. As a part of the mononuclear phagocyte system, it metabolizes hemoglobin removed from senescent red blood cells. The globin portion of hemoglobin is degraded to its constitutive amino acids, and the heme portion is metabolized to bilirubin, which is removed in the liver. The spleen houses antibody-producing lymphocytes in its white pulp and monocytes which remove antibody-coated bacteria and antibody-coated blood cells by way of blood and lymph node circulation. These monocytes, upon moving to injured tissue (such as the heart after myocardial infarction), turn into dendritic cells and m

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The hematopoietic system is a regenerative tissue with high cell turnover. Normal homeostasis of the hematopoietic system is insured by hematopoietic stem cells (HSCs). The important features of HSCs are the capacity to self-renew and multipotency. Multipotent HSCs perpetuate through life and are able to form all differentiated cell lineages of the blood. Most HSCs with long-term self-renewal capacity are quiescent and divide infrequently. However quiescent HSCs can be activated in response to injury. The signals responsible for the activation of quiescent HSCs are poorly investigated. The Trumpp laboratory has recently identified a role for IFNα in activation of quiescent HSCs in vivo. Activation of HSCs by IFNα involves increased phosphorylation of STAT1. Therefore the role of STAT1 in the homeostasis of the hematopoietic system was investigated by characterization of the hematopoietic system in STAT1-/- mice. A 2-fold decrease in short-term HSC (ST-HSCs) and multipotent progenitors (MPPs) was observed in the bone marrow of STAT1-/- mice compared to C57Bl/6 (wild type) mice. Analysis of progenitors of HSCs also revealed a small increase in common myeloid progenitors (CMPs) and a small decrease in common lymphoid progenitors (CLPs) in the bone marrow of STAT1-/- mice. These results indicate that STAT1 play a role in the homeostasis of ST-HSCs and MPPs in bone marrow. Functional analysis of STAT1-/- LT-HSCs using in vivo long-term reconstitution assay suggests that STAT1-/- LT-HSCs can reconstitute lethally irradiated mice. Nevertheless further investigations are necessary to examine whether STAT1 plays a role in HSCs self-renewal. The unexpected role of IFNα in activation of quiescent HSCs leads to the hypothesis that endogenously produced IFNα might be important for activation of HSCs in response to injury. To address this we generated the mouse model MxCre;R26REYFP to monitor endogenous IFNα/β production in the bone marrow after injury. Our results suggest that IFNα/β is produced in response to 5-FU induced myeloid suppression and G-CSF treatment in vivo. The role of IFNα/β during the recovery phase after 5-FU induced myeloid suppression was investigated using IFNAR-/- mice. These results suggest that endogenous IFNα/β might be important for the mobilization of HSCs into the spleen induced in response to 5-FU

2008

Conditional Deletion of Ferritin H in Mice Reduces B and T Lymphocyte Populations

Maike Jaworski, Liviu Vanoaica

The immune system and iron availability are intimately linked as appropriate iron supply is needed for cell proliferation, while excess iron, as observed in hemochromatosis, may reduce subsets of lymphocytes. We have tested the effects of a ferritin H gene deletion on lymphocytes. Mx-Cre mediated conditional deletion of ferritin H in bone marrow reduced the number of mature B cells and peripheral T cells in all lymphoid organs. FACS analysis showed an increase in the labile iron pool, enhanced reactive oxygen species formation and mitochondrial depolarization. The findings were confirmed by a B-cell specific deletion using Fth(lox/lox); CD19-Cre mice. Mature B cells were strongly under-represented in bone marrow and spleen of the deleted mice, whereas pre-B and immature B cells were not affected. Bone marrow B cells showed increased proliferation as judged by the number of cells in S and G2/M phase as well as BrdU incorporation. Upon in vitro culture with B-cell activating factor of the tumor necrosis factor family (BAFF), ferritin H-deleted spleen B cells showed lower survival rates than wild type cells. This was partially reversed with iron-chelator deferiprone. The loss of T cells was also confirmed by a T cell-specific deletion in Fth(lox/lox); CD4-Cre mice. Our data show that ferritin H is required for B and T cell survival by actively reducing the labile iron pool. They further suggest that natural B and T cell maturation is influenced by intracellular iron levels and possibly deregulated in iron excess or deprivation.

Public Library of Science2014

Differential Expression of NLRP3 among Hematopoietic Cells

Manuel Raphael Zenger

Although the importance of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in health and disease is well appreciated, a precise characterization of NLRP3 expression is yet undetermined. To this purpose, we generated a knock-in mouse in which the Nlrp3 coding sequence was substituted for the GFP (enhanced GFP [egfp]) gene. In this way, the expression of eGFP is driven by the endogenous regulatory elements of the Nlrp3 gene. In this study, we show that eGFP expression indeed mirrors that of NLRP3. Interestingly, splenic neutrophils, macrophages, and, in particular, monocytes and conventional dendritic cells showed robust eGFP fluorescence, whereas lymphoid subsets, eosinophils, and plasmacytoid dendritic cells showed negligible eGFP levels. NLRP3 expression was highly inducible in macrophages, both by MyD88- and Trif-dependent pathways. In vivo, when mice were challenged with diverse inflammatory stimuli, differences in both the number of eGFP-expressing cells and fluorescence intensity were observed in the draining lymph node. Thus, NLRP3 levels at the site of adaptive response initiation are controlled by recruitment of NLRP3-expressing cells and by NLRP3 induction. The Journal of Immunology, 2011, 186: 2529-2534.

2011