A dinâmica transitória do nicho de macrófagos hepáticos durante a lesão hepática aguda torna o organismo susceptível a infecções sistêmicas

Abstract

Kupffer cells are the primary liver resident immune cell responsible for metabolic and immune functions in the organ as they are strategically positioned inside the liver sinusoid with intimate contact with the blood. In the absence of these cells, the liver injury outcome is worsened. For instance, during acute liver injury promoted by acetaminophen overdose, they are responsible for limiting the damage and promoting the resolution of inflammation. In addition, acetaminophen overdose is responsible for the majority of acute liver failure cases that can evolve to fatal outcomes, which are usually driven by an uncontrolled inflammatory response that leads to organ disfunction. The dysfunction also affects the Kupffer cells, for instance, there is a massive reduction in the Kupffer cell population along with impairment of their functioning during tissue damage. As a consequence, during acute liver injury, clearance of dangerous self/non-self-molecules and pathogens might be significantly impaired. This disruption in the tissue-resident macrophage's niche may lead to a window of susceptibility to systemic infections, which represents a significant cause of mortality in acute liver failure patients. Besides that, the knowledge about Kupffer cell niche disruption and susceptibility to systemic infections are not fully understood. Here, we sought to define the dynamic of tissue-resident macrophage niche using a mice model for acute liver injury induced by acetaminophen overdose. During the acute phase, a massive reduction of Kupffer cells occurs in the necrotic areas opening the niche for infiltration of other cells. The Kupffer cell death was followed by a significant infiltration of inflammatory monocytes in the same region, transiently occupying the niche at the peak of inflammation. Following the acute liver injury kinetics, as the injury starts to resolve, there is a transition in the monocyte subset from proinflammatory to a pro-resolutive phenotype. Moreover, the remaining Kupffer cells were observed forming replicating cell clusters closer to areas devoid of Kupffer cells. So, the niche is occupied by dual input of proliferating Kupffer cells and monocytes. However, mice were still susceptible to infections despite the monocytic infiltration and the remaining Kupffer cells in the liver. The systemic infections were not blocked in the acute stage due to inefficient internalization and the elimination of circulating bacteria by the professional phagocytes. That stands out as a necessity to restore the niche in terms of functioning. Thus, cell therapy with bone marrow-derived macrophages (BMDM) was used as a relevant approach to occupy the niche opened after Kupffer cell demise with mature macrophages. BMDM rapidly reach the organ and are precisely positioned within necrotic areas, eliciting the reduction in necrotic areas and earlier transition to a resolutive environment. Likewise, the liver firewall function was restored after the cell therapy, as the BMDM-treated mice presented an improved bacterial removal from blood. Expanding our understanding of the dynamics of the Kupffer cell niche during liver inflammation is vital for the development of new therapeutic approaches such as cell therapy with bone marrow-derived macrophages. Therefore, we showed that the disruption in the Kupffer cell niche and its functioning during acute liver injury is a key element for secondary infections. We propose that the modulation of the macrophage niche is a promising therapeutic strategy for liver injuries that promote Kupffer Cell depletion.