B lymphopoiesis arrests precipitously in rabbits such that by 2–4 mo of age, before sexual maturity, little to no B lymphopoiesis occurs in the bone marrow (BM). Previously, we showed that in mice, adipocytes inhibit B lymphopoiesis in vitro by inducing inflammatory myeloid cells, which produce IL-1β. In this study, we characterized rabbit BM after the arrest of B lymphopoiesis and found a dramatic increase in fat, increased CD11b+ myeloid cells, and upregulated expression of the inflammatory molecules, IL-1β and S100A9, by the myeloid cells. We added BM fat, CD11b+ myeloid cells, and recombinant S100A9 to B lymphopoiesis cultures and found that they inhibited B lymphopoiesis and enhanced myelopoiesis. Unlike IL-1β, which inhibits B lymphopoiesis by acting on early lymphoid progenitors, S100A9 inhibits B lymphopoiesis by acting on myeloid cells and promoting the release of inflammatory molecules, including IL-1β. Many molecules produced by adipocytes activate the NLRP3 inflammasome, and the NLRP3 inhibitor, glibenclamide, restored B lymphopoiesis and minimized induction of myeloid cells induced by adipocyte-conditioned medium in vitro. We suggest that fat provides an inflammatory microenvironment in the BM and promotes/activates myeloid cells to produce inflammatory molecules such as IL-1β and S100A9, which negatively regulate B lymphopoiesis.
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This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant AI068390 and by National Institutes of Health/National Institute on Aging Grant F31AG047817.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- adipocyte-conditioned medium
- bone marrow
- BM fat–CM
- BM fat–conditioned medium
- common lymphoid progenitor
- hematopoietic stem cell
- myeloid-derived suppressor cell
- multipotent progenitor
- quantitative RT-PCR
- stem cell factor.
- Received September 21, 2016.
- Accepted February 27, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.