Inhibition of B Lymphopoiesis by Adipocytes and IL-1-Producing Myeloid-Derived Suppressor Cells.
B lymphopoiesis declines with age, and this decline correlates with increased adipose tissue in the bone marrow (BM). Also, adipocyte-derived factors are known to inhibit B lymphopoiesis. Using cocultures of mouse BM cells with OP9 stromal cells, we found that adipocyte-conditioned medium induces the generation of CD11b(+)Gr1(+) myeloid cells, which inhibit B cell development in vitro. Adipocyte-conditioned medium-induced CD11b(+)Gr1(+) cells express Arg1 (arginase) and Nos2 (inducible NO synthase) and suppress CD4(+) T cell proliferation, indicating that these cells are myeloid-derived suppressor cells (MDSCs). Blocking arginase and inducible NO synthase did not restore B lymphopoiesis, indicating that inhibition is not mediated by these molecules. Transwell and conditioned-medium experiments showed that MDSCs inhibit B lymphopoiesis via soluble factors, and by cytokine array we identified IL-1 as an important factor. Addition of anti-IL-1 Abs restored B lymphopoiesis in BM cultures containing MDSCs, showing that MDSC inhibition of B lymphopoiesis is mediated by IL-1. By treating hematopoietic precursors with IL-1, we found that multipotent progenitors are targets of IL-1. This study uncovers a novel function for MDSCs to inhibit B lymphopoiesis through IL-1. We suggest that inflammaging contributes to a decline of B lymphopoiesis in aged individuals, and furthermore, that MDSCs and IL-1 provide therapeutic targets for restoration of B lymphopoiesis in aged and obese individuals.
Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.
Domenick E
DE
Kennedy
Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153 kknight@luc.edu.
Katherine L
KL
Knight
D017667:Adipocytes / Q000166:cytology* / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001119:Arginase / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000068884:Immunosenescence / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D038041:Lymphopoiesis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis
D000906:Antibodies; D039481:CD11b Antigen; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase