Abstract
BackgroundAlteration in the immune system is one of the most profound aspects of aging. Progressive changes in the number of B lymphocyte progenitors during aging have been reported but the underlying mechanisms are still elusive. A heterozygous G608G mutation in the LMNA gene leads to a deletion of 50 amino acids in lamin A protein, termed progerin, and is the predominant cause of Hutchinson-Gilford progeria syndrome (HGPS). Lack of Zmpste24, a metalloproteinase responsible for prelamin A processing, leads to progeroid features resembling HGPS. Therefore Zmpste24-deficient mice provide an ideal mouse model to study the impact of lamin A and (premature) aging on the aging-related decline of B lymphopoiesis.ResultsAnalysis of bone marrow (BM) nucleated cells revealed a decline of early B cell progenitors in Zmpste24−/− mice. BM transplantation in a congenic strain completely rescued the defects in B lymphopoiesis, indicating that the decline in B cell progenitors in Zmpste24−/− mice is attributable to defective BM microenvironments rather than to cell-intrinsic defects. Further investigation revealed downregulation of a set of important early B lymphopoiesis factors in Zmpste24−/− bone marrow stromal cells (BMSCs), such as Vcam-1, SDF-1α, Flt3L and TSLP, and most of them are under transcriptional control of NF-κB signaling. Though TNFα stimulates IκBα degradation and NF-κB nuclear translocation in Zmpste24−/− BMSCs, NF-κB fails to stimulate IκBα re-expression, which mediates a negative feedback loop of NF-κB signaling in wild-type BMSCs.ConclusionsOur data demonstrate a cell-extrinsic defect of B cell development in a progeroid mouse model and a critical role for lamin A in the regulation of NF-κB signaling and cytokines that are essential for lymphopoiesis.
Highlights
Alteration in the immune system is one of the most profound aspects of aging
While 1-month-old Zmpste24−/− mice had a similar profile of early B cells to that of their heterozygous littermates, Zmpste24−/− mice of 3 months and 5 months of age showed a significant decrease in the number of B lymphocytes as well as the percentage of progenitor B (pro-B) and B cell precursors (pre-B) populations (Figure 1B-D), suggesting a defect in the generation of B lineage lymphocyte progenitors, which is consistent with the previous reports on physiologically senescent mice [30,31,32]
These results indicate that the defects observed in early B cell development in Zmpste24-deficient mice are not cell-intrinsic, but rather the consequence of a defective bone marrow (BM) microenvironment
Summary
Progressive changes in the number of B lymphocyte progenitors during aging have been reported but the underlying mechanisms are still elusive. Results: Analysis of bone marrow (BM) nucleated cells revealed a decline of early B cell progenitors in Zmpste24−/− mice. Alteration in the immune system is one of the most profound aspects of aging, including shrinkage of the diverse repertoire of immunoglobins in both B and T lymphocytes [2,3], compromised immune responsiveness to pathogens, which is marked by greater proportion of low-affinity antibodies and involves both humoral and cell-mediated immune response [4,5], and increased auto-reactive cells leading to higher risk of autoimmune diseases [6].
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