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

Abstract

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 (c-fms, pu.1, runx) are enhanced, and lymphoid genes (flt3, e47, ebf) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after only six 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 in obesity-driven BM malfunction and demonstrate the importance of LPS. Our findings raise important questions about the impact of maternal obesity and endotoxemia to fetal hematopoiesis since fetal immune precursors are also sensitive to TLR4 signals.