Compromised emergency hematopoiesis in obesity requires TLR4

Abstract

Abstract Following acute injury/infection, bone marrow (BM) precursors must responsively redirect from steady-state to emergency hematopoiesis. Prospective and retrospective studies establish obesity as risk factor for infection but the mechanisms are poorly understood. Here, we show in a murine model of obesity that moderate changes in steady-state BM hematopoiesis become exaggerated during hematopoietic duress. At steady-state, diet-induced obese mice have a 30% decrease in BM hematopoietic stem cells (HSCs) with a parallel increase in splenic HSCs. HSCs are functionally competent in vitro and following competitive transfer in vivo. BM lymphoid and myeloid progenitors in obese mice are numerically intact but the transcriptional profiles and differentiation potential are strikingly myeloid-biased, accompanied by myeloid skewing of peripheral blood. Responses to acute hematopoietic challenge are deficient. Emergency hematopoiesis following chemotherapeutic ablation is reduced 60% in obesity. Likewise, emergency myelopoiesis in response to endotoxin is characterized by accumulation of immature rather than mature myeloid cells in obese mice. The obesity-associated inflammatory environment plays a key role as transfer of obese BM to lean recipients restores emergency immune response to chemotherapeutic challenge. Moreover, mice deficient in toll-like receptor 4 (TLR4), a central regulator of inflammation, retain robust hematopoietic rebound responses despite diet-associated weight gain. Thus, in obesity, moderate changes in steady-state blood cell production mask major defects in hematopoietic stress responses, via a TLR4-dependent mechanism.