Microbiota and Neutrophil Development

Microbiota, Neutrophil Development, and Sickle Cell Disease Pathogenesis

Paul S. Frenette

RuthL. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, USA

Real-time intravital microscopy analyses in humanized models of sickle cell disease (SCD) have uncovered a critical role for neutrophils in mediating vaso-occlusive episodes. Peripheral blood neutrophils are recruited in inflamed venules via the interactions of the selectin adhesion molecules (E- and P-selectin) with their ligands. These molecules mediate neutrophil rolling on the vessel wall allowing interactions with chemokines and integrins which lead to firm leukocyte adhesion. Firmly adherent neutrophils are functionally heterogenous. For example, only a subset of adherent neutrophils is capable of capturing free-flowing red blood cells (RBCs). The interactions between RBCs and adherent neutrophils lead to reductions of blood flow and promote vaso-occlusion. Recent studies show that neutrophil heterogeneity is dictated at least in part by the leukocyte's age. Older neutrophils that have spent more time in the circulation exhibit increased pro-inflammatory properties (e.g. adhesion, neutrophil extracellular trap formation, capacity to capture RBCs). The aging of neutrophils is regulated by the microbiota in that it is delayed in mice treated with broad-spectrum antibiotics. Wild-type mice kept in the germfree environment show lower aged neutrophil counts. SCD children (<5 years old) taking prophylactic Penicillin V have lower aged neutrophil counts than those off Penicillin V. Antibiotics also reduce chronic organ damage in SCD mice. Psychogenic stress is often reported by SCD patients as a trigger for vaso-occlusive episodes. We have recently tested the mechanisms of psychogenic stress on SCD vaso-occlusion and will present unpublished data linking signals from the brain regulating gut microbiota, hematopoiesis, and the innate immune response.