Regulation of neutrophil heterogeneity and the hematopoietic stem cell niche by inter-organ communications

Abstract

Neutrophils provide immune protections against invading pathogens but may also promote tissue injury in inflammatory diseases. Under steady-state conditions, neutrophil heterogeneity may arise from aging and the replenishment by newly released neutrophils from the bone marrow. Here, we show using in vivo aging analyses that the neutrophil pro-inflammatory activity correlates positively with their aging in the circulation. Aged neutrophils represent an overly active subset that exhibits enhanced aM132 integrin (Mac-1) activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil aging is driven by the microbiota through neutrophil Toll-like receptors (TLRs) and myeloid differentiation factor 88 (Myd88)-mediated signaling pathways. Microbiota depletion significantly reduces the number of aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle cell disease or endotoxin-induced septic shock.;In this manuscript, we also characterize several aspects of neural regulation in the hematopoietic stem cell (HSC) niche. We describe that constitutive circadian recruitment of leukocytes to tissues is regulated by the sympathetic nervous system through modulating adhesion molecule expression on endothelial cells. Circadian recruitment of neutrophils and their rhythmic clearance in the bone marrow enables circadian modulation of specific cellular constituents of the HSC niche, leading to rhythmic release of HSCs into the circulation. In addition, we have observed that acute myelogenous leukemia severely disrupts sympathetic innervation of the arterioles in the bone marrow, leading to a significantly transformed niche.;In conclusion, biological systems maintain a complex regulatory network not only at the molecular level, but also at the cellular and inter-organ levels. Our results identify a role for the microbiota in regulating neutrophil aging in the circulation, and for the sympathetic nervous system in regulating both healthy and malignant HSC niche. Advances in understanding of these inter-organ communications may provide novel therapeutic targets for inflammatory and hematopoietic disorders.