Consequence of LIVer sinusoidal Endothelial cells ageing on Liver ImmunitY – LIVELY

Infection in the ageing population is a major public health concern. Age is independently associated with adverse outcomes in infectious diseases, with the elderly population accounting for 80% of sepsis-related deaths. The accumulation of senescent cells can drive many age-associated phenotypes. The liver has the highest proportion of age-induced senescent cells, the majority of which are liver sinusoidal endothelial cells (LSECs). LSECs are unique, highly specialised fenestrated endothelial cells that display the highest endocytosis capacity of any human cell, serve as sentinel cells to detect microbial infection through activation of pattern recognition receptors and as antigen cross-presenting cells, and thus have unique immune properties. I obtained preliminary data by analysing publicly available transcriptomic data of senescent LSECs showing that LSECs function most impacted by senescence was their immune function and in particular their interactions with lymphocytes. I have shown in vitro that senescent LSECs display a pro-inflammatory phenotype in response to antigens, when compared to young LSECs. In addition, preliminary results from in vivo infection models in mice (old and young and in a novel mouse model of LSECs-specific accelerated senescence) indicate that the aged liver response to bacterial infection is impaired and that senescent LSECs may indeed be key factors modulating the aged liver response to bacterial infection. Based on these fundings, I hypothesize that LSECs senescence impairs liver immunity during ageing and promotes excessive inflammatory responses, thereby promoting the severity of infectious diseases. I will test this hypothesis along 3 aims: 1/ Investigate the effects of senescence on LSECs on liver immune response, under basal and under infections conditions by using in vitro and in vivo experiments; 2/ Assess the consequences of senescent LSECs on infection severity using in vivo experimental models in mice with LSECs accelerated senescence (already established and validated); 3/ Explore strategies for reversing aged-induced impairment of LSECs immune function to limit infection severity, employing senolytic strategies.
The consequences of age-related senescence within the liver in infectious diseases, such as sepsis, remain largely unknown. This project will provide insights into how senescent LSECs might modulate the immune response to bacterial infections and unravel impaired mechanisms and modulators induced by ageing LSECs, that could be targeted as novel therapeutic approaches to reduce the severity of sepsis in the elderly population.