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

Ailing Liu,Lisa Borghesi,Maja Stefanovic-Racic,Willi Jahnen-Dechent,Rashmi Kumar,Robert M O’Doherty,Ying Ding,Minhui Chen

doi:10.1038/s41467-018-03145-8

Abstract

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.

Highlights

Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function
Cell-intrinsic toll-like receptor 4 (TLR4) is required for LKSneg and common lymphoid progenitors (CLPs) malfunction during stages of obesity when gross BM inflammation is not readily detectable
We show that the TLR4 ligand LPS is elevated in the plasma of obese animals, and administration of exogenous LPS in lean mice recapitulates BM LKSneg and CLP functional alterations

Summary

Introduction

A prevalent condition in adults and children, impairs bone marrow (BM) function. Lean mice exposed to the TLR4 ligand lipopolysaccharide (LPS) at doses similar to that detectable in obese serum recapitulates BM lymphomyeloid alterations Together, these results establish a mechanistic contribution of BM cellintrinsic TLR4 to obesity-driven BM malfunction and demonstrate the importance of LPS. Following encounter with TLR ligand, these migratory HSPCs quickly boost the local supply of myeloid cells[21].The implications of this BM TLR4 sensing pathway to obesity-associated BM malfunction have not been directly examined. Lipopolysaccharide (LPS) and dietary saturated fatty acids are two TLR4 ligands recognized as potentially important in obesity-associated changes in metabolism and immune function[22,23,24]. The in vivo importance of this pathway of TLR4 activation is controversial as saturated fatty acids are generally considered to be weak TLR4 ligands relative to LPS11,15,26

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Results

Conclusion