Estudo da origem, localização e função de fagócitos durante o repovoamento hepático

Abstract

Macrophages and dendritic cells are phagocytes present in almost all tissues in mammals and play a pivotal role for tissue homeostasis and during immune responses. Liver phagocytes play a vital role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. However in catastrophic events including trauma, infections or toxin ingestion, many of the liver phagocytes can be wiped out leaving large areas devoid of these cells. Here we used a unique combination of mass cytometry (Time of flight mass cytometry - CyTOF), gene expression and liver intravital approaches to precisely determine phagocytic populations within the liver and the functional consequences of their replenishment by myeloid precursors. While Kupffer cells were exclusively located in the sinusoidal lumen, we identified a previously unknown population of dendritic cells that was mainly located under the liver capsule. After full depletion of dendritic and Kupffer cells, intravascular myeloid precursors replenished location, density and function of both populations. However, we also discovered that these emergency repopulated livers were dysfunctional in their ability to respond to injury and to clear bacteria for at least 30 days, which might have a huge impact in how hepatitis patients are treated. After this “educational period”, these new phagocytes returned to normal response to injury and bacterial trapping. Conclusions: Our data shed light on the liver’s ability to locally shape phagocyte precursors into two vastly different immune cells localized to two fundamentally different tissue compartments, and opened new perspectives in the relevance of the immune- based approach in gastroenterology practice regarding to liver injured patients.