Inflammatory Changes in Bone Marrow Microenvironment Associated with Declining B Lymphopoiesis.
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.
Department of Microbiology and Immunology, Loyola University, Chicago, IL 60153.
Domenick E
DE
Kennedy
Department of Microbiology and Immunology, Loyola University, Chicago, IL 60153 kknight@luc.edu.
Katherine L
KL
Knight
D000273:Adipose Tissue / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001854:Bone Marrow Cells / Q000502:physiology*; D039481:CD11b Antigen / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism*; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D005905:Glyburide / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects; D051379:Mice; D038042:Myelopoiesis / Q000187:drug effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors; D011817:Rabbits
D039481:CD11b Antigen; D040502:Calgranulin B; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D005905:Glyburide