Immature neutrophil migration promotes inflammation during obesity

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT SUMMARY Obesity is associated with chronic, systemic, and low-grade inflammation that contributes to the development of comorbidities such as metabolic disease. Anti-inflammatory agents have been shown to improve metabolic markers in obese mice and humans, thus understanding the mechanistic drivers of inflammation during obesity is critical to developing new treatments. During obesity, myeloid cells, including monocytes, macrophages, and neutrophils, accumulate in the circulation and metabolic tissues and drive metabolic dysfunction by inhibiting insulin signaling and promoting tissue fibrosis. Bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) are dysregulated by obesity to favor the generation of myeloid cells at the expense of reduced lymphoid cell output, driving systemic inflammation. Data from mice indicate that these alterations to the BM are long-lasting and persist even after weight loss, which likely contributes to the worsened inflammatory outcomes that are observed in mice and humans that regain weight. To determine how the hematopoietic system is altered by obesity, I performed single-cell RNA sequencing on HSPCs from lean and diet-induced obesity (DIO) mice. Stem cells from DIO mice are enriched for genes related to cell cycle and DNA repair, suggesting dysregulation of their quiescent cycle. Immature neutrophils, marked by histidine decarboxylase (Hdc), are key regulators of stem cell quiescence by secreting histamine, but are recruited out of the bone marrow in DIO. These data suggest that immature neutrophil migration promotes HSPC dysfunction in DIO, representing a possible therapeutic target for treating obesity-associated inflammation. In this proposed project, I will (Aim 1) determine how inhibiting the movement of immature neutrophils during obesity affects HSPCs, metabolism, and systemic inflammation. I will then (Aim 2) determine how immature neutrophils migrate during weight loss, how this affects myelopoiesis, and if inhibiting their migration during weight loss improves metabolic and inflammatory outcomes. Our lab brings strong expertise in stem cell biology, disease modeling, and therapeutic testing, and with support of experts in hematopoiesis and obesity, I believe that the proposed project will further our understanding of the complex interactions between the hematopoietic system, inflammatory cells, and metabolic organs during obesity.