3082 – NONALCOHOLIC STEATOHEPATITIS PROMOTES EMERGENCY MYELOPOIESIS AND IMMUNE EFFECTOR DYSFUNCTION

Abstract

Neutrophils and macrophages act as sentinels and help protect against injury and infection. Emergency myelopoiesis is triggered during this process and increases production of myeloid cells from hematopoietic stem and progenitor cells (HSPCs). This process is largely studied under acute stressors such as infection, but the impact of organ-specific inflammation on emergency myelopoiesis is poorly explored. Metabolic disorders induce metainflammation, a low-grade systemic chronic inflammation that results in elevated myeloid cells in circulation. The link of metainflammation to emergency myelopoiesis is not understood. We examined emergency myelopoiesis and immune cell function in a zebrafish model for Nonalcoholic steatohepatitis (NASH), an aggressive, pro-inflammatory hepatic manifestation of metabolic syndrome. To induce NASH, zebrafish larvae were fed a high-cholesterol diet for 1 week leading to liver steatohepatitis and chronic systemic inflammation. We detected increased proliferation of hematopoietic progenitors, as evidenced by increased 5-ethynyl-2’deoxyuridine (5-EdU) incorporation in hematopoietic tissues. Consistent with these findings, cd41:GFP-positive HSPCs as well as the total number of neutrophils and macrophages were increased in NASH larvae when compared to larvae fed with normal diet. In addition, neutrophils from NASH larvae displayed a hyperactive and dysfunctional response, as evidenced by exacerbated recruitment of lyz:H2B-mCherry-positive neutrophils to a tailfin injury. Neutrophils in NASH zebrafish also had increased speed, delayed resolution, and increased neutrophil reactive oxygen species production at the injury site. These data suggest that metabolic disorders, such as NASH, can promote emergency myelopoiesis and immune effector dysfunction leading to a host of inflammatory deregulation in these individuals. Neutrophils and macrophages act as sentinels and help protect against injury and infection. Emergency myelopoiesis is triggered during this process and increases production of myeloid cells from hematopoietic stem and progenitor cells (HSPCs). This process is largely studied under acute stressors such as infection, but the impact of organ-specific inflammation on emergency myelopoiesis is poorly explored. Metabolic disorders induce metainflammation, a low-grade systemic chronic inflammation that results in elevated myeloid cells in circulation. The link of metainflammation to emergency myelopoiesis is not understood. We examined emergency myelopoiesis and immune cell function in a zebrafish model for Nonalcoholic steatohepatitis (NASH), an aggressive, pro-inflammatory hepatic manifestation of metabolic syndrome. To induce NASH, zebrafish larvae were fed a high-cholesterol diet for 1 week leading to liver steatohepatitis and chronic systemic inflammation. We detected increased proliferation of hematopoietic progenitors, as evidenced by increased 5-ethynyl-2’deoxyuridine (5-EdU) incorporation in hematopoietic tissues. Consistent with these findings, cd41:GFP-positive HSPCs as well as the total number of neutrophils and macrophages were increased in NASH larvae when compared to larvae fed with normal diet. In addition, neutrophils from NASH larvae displayed a hyperactive and dysfunctional response, as evidenced by exacerbated recruitment of lyz:H2B-mCherry-positive neutrophils to a tailfin injury. Neutrophils in NASH zebrafish also had increased speed, delayed resolution, and increased neutrophil reactive oxygen species production at the injury site. These data suggest that metabolic disorders, such as NASH, can promote emergency myelopoiesis and immune effector dysfunction leading to a host of inflammatory deregulation in these individuals.