Bone Marrow Plasma Cells Modulate Local Myeloid-Lineage Differentiation via IL-10

Abstract

Bone marrow plasma cells have been reported to represent a major source of IL-10; however, the impact of plasma cell derived IL-10 in that tissue remains poorly understood. We confirm in this study that even in the absence of acute immune reactions, mature plasma cells represent the dominant IL-10+ cell population in the bone marrow, and identify myeloid-lineage cells as a main local target for plasma cell derived IL-10. Using Vert-X IL-10 transcriptional reporter mice, we found that more than 50% of all IL-10+ cells in bone marrow were CD138+ plasma cells, while other IL-10+ B lineage cells were nearly absent in this organ. Accordingly, IL-10 was found in the supernatants of short-term cultures of FACS-sorted bone marrow plasma cells, confirming IL-10 secretion from these cells. IL-10+ bone marrow plasma cells showed a B220−/CD19−/MHCII low phenotype suggesting that these cells represent a mature differentiation stage. Approximately 5% of bone marrow leucocytes expressed the IL-10 receptor (IL-10R), most of them being CD115+/Ly6C+/CD11c− monocytes. Compared to littermate controls, young B lineage specific IL-10 KO mice showed increased numbers of CD115+ cells but normal populations of other myeloid cell types in bone marrow. However, at 7 months of age B lineage specific IL-10 KO mice exhibited increased populations of CD115+ myeloid and CD11c+ dendritic cells (DCs), and showed reduced F4/80 expression in this tissue; hence, indicating that bone marrow plasma cells modulate the differentiation of local myeloid lineage cells via IL-10, and that this effect increases with age. The effects of B cell/plasma cell derived IL-10 on the differentiation of CD115+, CD11c+, and F4/80+ myeloid cells were confirmed in co-culture experiments. Together, these data support the idea that IL-10 production is not limited to early plasma cell stages in peripheral tissues but is also an important feature of mature plasma cells in the bone marrow. Moreover, we provide evidence that already under homeostatic conditions in the absence of acute immune reactions, bone marrow plasma cells represent a non-redundant source for IL-10 that modulates local myeloid lineage differentiation. This is particularly relevant in older individuals.

Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

“…These data lend strong support to a model where LLPCs generated from acute immunizations destined for bone marrow niches can survive in peripheral sites and secrete antigen-specific antibodies for extended periods of time (117). Hence, PC localization in bone marrow niches may play other roles that are independent of antibody secretion (118,119).…”

Hematopoietic Multipotent Progenitors and Plasma Cells: Neighbors or Roommates in the Mouse Bone Marrow Ecosystem?

“…Recently, two studies reported that PC accumulation with age regulates the production of inflammatory factors by BM stromal cells, which in turn promotes myeloid-biased HSCs (144,145). This impact on myeloid cells is probably due to the ability of PCs to produce IL-10, one of the key drivers of the myeloid differentiation (145,146). Consequently, both studies suggest a potential impact of PCs on MSCs and on the skewing of MPPs toward myeloid lineage with age (10).…”

“…It is known that both myelopoiesis and the number of PCs increase with aging in the BM. Recently, two studies reported that PC accumulation with age regulates the production of inflammatory factors by BM stromal cells, which in turn promotes myeloid-biased HSCs (144,145). This impact on myeloid cells is probably due to the ability of PCs to produce IL-10, one of the key drivers of the myeloid differentiation (145,146).…”

Plasma Cells, the Next Generation: Beyond Antibody Secretion

“…Pharmacological blockade of IL-1 and tumor necrosis factor-alpha (TNF-α) signaling reduced granulopoiesis in aged mice demonstrating the importance of these factors in the age-associated increase in myelopoietic output (17). Notably, a recently published study (16) demonstrated that in vitro derived mouse PCs had the potential to regulate the composition of myeloid cells generated in culture. Here, IL-10 was the critical regulator that skewed the myeloid compartment toward a more macrophage-like cell fate (16).…”

“…Notably, a recently published study (16) demonstrated that in vitro derived mouse PCs had the potential to regulate the composition of myeloid cells generated in culture. Here, IL-10 was the critical regulator that skewed the myeloid compartment toward a more macrophage-like cell fate (16).…”