Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4

Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here, we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes ( Csf1r , Spi1 ,...

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Bibliographic Details
Published in:Nature communications Vol. 9; no. 1; pp. 708 - 11
Main Authors: Liu, Ailing, Chen, Minhui, Kumar, Rashmi, Stefanovic-Racic, Maja, O’Doherty, Robert M., Ding, Ying, Jahnen-Dechent, Willi, Borghesi, Lisa
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 16.02.2018
Nature Publishing Group
Nature Portfolio
Subjects:
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Adoptive Transfer
Adults
Animals
Bone marrow
Bone Marrow - physiopathology
Children
Emergency response
Endotoxemia
Fetuses
Genes
Hematopoiesis
Hematopoietic Stem Cells - metabolism
Hemopoiesis
High fat diet
Humanities and Social Sciences
Immune response
Immune system
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
multidisciplinary
Obesity
Obesity - immunology
Obesity - metabolism
Obesity - physiopathology
Precursors
Proteins
Rodents
Runx1 protein
Science
Science (multidisciplinary)
TLR4 protein
Toll-Like Receptor 4 - physiology
Toll-like receptors
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here, we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes ( Csf1r , Spi1 , Runx1 ) are enhanced, and lymphoid genes ( Flt3 , Tcf3 , Ebf1 ) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after 6 weeks of high-fat diet and depends on precursor cell-autonomous TLR4. Further, lean mice exposed to the TLR4 ligand lipopolysaccharide (LPS) at doses similar to that detectable in obese serum recapitulates BM lympho-myeloid alterations. Together, these results establish a mechanistic contribution of BM cell-intrinsic TLR4 to obesity-driven BM malfunction and demonstrate the importance of LPS. Our findings raises important questions about the impact of maternal obesity and endotoxemia to fetal hematopoiesis, as fetal immune precursors are also sensitive to TLR4 signals. Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-03145-8