Accumulation of prelamin A compromises NF-κB-regulated B-lymphopoiesis in a progeria mouse model.

Abstract

BACKGROUND:

Alteration 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.

RESULTS:

Analysis 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.

CONCLUSIONS:

Our 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.

• Authors: Baohua Liu, Shuangcheng Zhou, Xinguang Liu, Keyuan Zhou, Fengju Zhang, Zhongjun Zhou
• Journal: Longevity & healthspan (Longev Healthspan) Vol. 2 Pg. 1 ( 2013) ISSN: 2046-2395 [Print] England
• PMID: 24764515 (Publication Type: Journal Article)