Dinâmica de fagócitos mononucleares hepáticos

Abstract

Liver-resident macrophages are replaced by monocyte-derived macrophages (MDMs) during infections, drug-induced liver injury, exposure to radiation and other liver diseases. Here we investigate the dynamics of replenishment of hepatic macrophages after their total depletion, and possible consequences of the resident cells Kupffer cells (KCs) replacement with MDMs. Using intravital microscopy (IVM), we observe that KCs preferably occupy sinusoidal areas in compared to pericentral areas. After total depletion by i.v. injection of clodronate (CLL), hepatic repopulation takes place gradually, reaching the original distribution around 15 days after depletion. To investigate the dynamics of hepatic macrophages during liver damage, we follow the dynamics of F4/80+ cells during the response to aggression caused by toxic overdose of acetaminophen (APAP). This treatment causes severe liver damage, which is evidenced by high levels of serum transaminases (alanine aminotransferase - ALT), accompanied by reduced liver function, which is measured through the cleansing of Indocyanine Green. In addition , the inflammatory process causes partial depletion of KCs in acute stage (24 hours) followed by a significant increased and reverse pattern of the liver macrophages distribution, leading to a stage in which most cells are located in pericentral areas. Interestingly, in both depletion models (total and partial), the number and location of hepatic macrophages are restored, suggesting the existence of a regulatory pathway to control and maintain hepatic cells population. Besides, Kupffer cells present a regulatory role in original inflammatory processes, once mice with depletion of KCs showed worse injury when treated with APAP. This is consistent with data that showed that animals with depletion and, then, repopulation (after 15 and 60 days) and treated with APAP still present abnormal patterns of injury and hepatic function during the inflammatory process compared to the animals without depletion, also treated with APAP. Animals with depletion have more sensitive resident macrophages to acute inflammation stage and less accumulation of F4/80+ cells on the third day after treatment, denoting more static behavior or a loss in the recruitment of monocytes. Therefore, we conclude that the original KCs play regulatory functions during liver damage, and MDMs do not take anti-inflammatory and migratory phenotype like the original cells do.