Accumulation of prelamin A compromises NF-κB-regulated B-lymphopoiesis in a progeria mouse model.
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.
Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong ; Guangdong Medical College, 1 Xin Cheng Avenue, Dongguan, 523808, China.
Baohua
B
Liu
Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
Shuangcheng
S
Zhou
Guangdong Medical College, 1 Xin Cheng Avenue, Dongguan, 523808, China.
Xinguang
X
Liu
Guangdong Medical College, 1 Xin Cheng Avenue, Dongguan, 523808, China.
Keyuan
K
Zhou
Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Fengju
F
Zhang
Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
Zhongjun
Z
Zhou
Aging; B-lymphopoiesis; Hutchinson-Gilford progeria syndrome (HGPS); Lamin A; NF-κB; Zmpste24