Bone marrow hematopoietic stem and progenitor cells (BM HSPCs) express innate immune sensors for bacterial products including toll-like receptor 4 (TLR4). Unexpectedly, we recently demonstrated in a non- infectious setting that HSCs from TLR4 signaling deficient mice outcompete wild-type in competitive adoptive transfer. These findings open a new avenue of investigation into the role of basal TLR4 signals in steady-state hematopoiesis. Further, these observations raise questions about BM corruption in disease conditions marked by increased levels of circulating TLR4 ligands.
In Aim 1, we will use genome-wide approaches to determine the transcriptome and chromatin structure of TLR4-deficient versus -sufficient HSCs, an essential step toward identifying the molecular basis of functional changes.
Aim 2, we will perform separation-of-function experiments to distinguish the mechanistic importance of two distinct co-receptors, CD14 (LPS) versus Fetuin A (saturated fats), to TLR4-dependent HSPC lymphoid suppression in obesity, a disease of global burden. The outcomes of these studies will significantly advance our understanding of how environmental cues delivered through a hallmark innate immune sensor shape BM hematopoietic processes.
Blood cell production is shaped by cues from the environment. These studies address how the activity of blood cell precursors changes in response to environmental cues delivered through one major sensing pathway.
|Liu, Ailing; Chen, Minhui; Kumar, Rashmi et al. (2018) Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4. Nat Commun 9:708|