Inhibition of B Lymphopoiesis by Adipocytes and IL-1-Producing Myeloid-Derived Suppressor Cells

J Immunol. 2015 Sep 15;195(6):2666-74. doi: 10.4049/jimmunol.1500957. Epub 2015 Aug 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / immunology
  • Animals
  • Antibodies / pharmacology
  • Arginase / biosynthesis
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • Bone Marrow Cells / cytology
  • CD11b Antigen / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Culture Media, Conditioned / pharmacology
  • Immunosenescence / immunology*
  • Inflammation / immunology
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / immunology*
  • Lymphocyte Activation / immunology
  • Lymphopoiesis / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Multipotent Stem Cells / immunology
  • Myeloid Cells / immunology
  • Nitric Oxide Synthase Type II / biosynthesis

Substances

  • Antibodies
  • CD11b Antigen
  • Culture Media, Conditioned
  • Interleukin-1
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Arg1 protein, mouse
  • Arginase