Bone Loss and TLR4 Signals Contribute Independently to B Lineage Aging

B cell development declines with age, but how structural changes in the marrow environment contribute to that process is incompletely understood. Multiplexed volumetric imaging revealed that B lineage cells were enriched near bone, and trabecular bone in particular, in young mice. However, B cell progenitors were depleted from these regions in strains of old mice that exhibited senile osteoporosis. In striking contrast, the age-related decline of B lymphopoiesis was attenuated in mice in which bone mass was maintained over the lifespan and could be completely abrogated by concomitantly blocking TLR4 signaling. In addition to demonstrating that developing B lineage cells are not randomly distributed in the marrow, these results indicate that the age-related decline in B lymphopoiesis is influenced by the loss of salutary and not just an increase in inhibitory signals.