Plasma cells are obligate enhancers of age-associated myeloid skewing

Abstract

Abstract In humans and mice, aging results in significantly elevated myelopoiesis and the increased production of inflammatory cytokines with age is thought to underlie this phenomenon. The observation that treatment of young mice with factors such as interleukin (IL)-1 can skew hematopoiesis towards myeloid development is consistent with this hypothesis. However, the cellular source(s) of inflammatory cytokines in the aging bone marrow has not been fully defined. We observed that plasma cells (PCs) accumulate in the bone marrow with age and acquire an inflammatory gene signature. Furthermore, we observed that their depletion in vivo using anti-CD138 antibodies resulted in a significant decline in myelopoiesis as demonstrated by a reduction in the number of myeloid biased hematopoietic stem cells, myeloid progenitors and mature myeloid cells. We also found that anti-CD138 treated mice exhibited reduced expression of genes encoding inflammatory cytokines in bone marrow stromal cells, indicating that plasma cells can regulate inflammatory cytokine production by other microenvironmental components. We tested whether this inflammatory network was necessary to drive age-associated myeloid skewing by treating old mice with Anakinra or Enbrel to abrogate IL-1 and tumor necrosis factor alpha (TNF-α) signaling, respectively. Concurrent blockade of both signaling pathways in old mice resulted in the significant reduction of bone marrow myelopoiesis, which was not observed upon inhibition of either pathway alone. These data demonstrate a previously unappreciated ability of inflammatory PCs to stimulate myelopoiesis and implicate them at the center of an inflammatory regulatory network in the aging bone marrow.