Impact of the apoptotic cell identity on macrophage function: A novel approach for the re-establishment of liver homeostasis upon damage

• Applicant: Lidia Bosurgi, Ph.D.
• Subject Area: Gastroenterology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513348670

Macrophages are professional phagocytes which constantly engulf apoptotic cells. In addition to phagocytosis, in each tissue macrophages acquire different functions, which are believed to be driven by the environment where they reside. However, the broad spectrum of activation states acquired within the same tissue during all lifespan, suggests that other signals play major roles in determining macrophage signature profile. We therefore hypothesize that the original identity of the apoptotic cells phagocytosed, commits macrophages toward a defined signature and function. Similar to the proverbial saying “Tell me what you eat and I will tell you who youare”, we believe that macrophages, as big eaters of the immune system, are shaped in their function by the type of meal they have. Of note, our preliminary data strongly indicate that a portfolio of different apoptotic cells sensed by macrophages confers different instructionsand thus is central to shape the different roles macrophages can acquire during an immune response. However, the impact of apoptotic cells with different identities on macrophages in vivo and the underlying molecular and cellular mechanisms is completely unknown. Importantly, whether interfering with the apoptotic cell-macrophage cross talk might affect the course of chronic liver infections induced by parasites, such as Schistosoma mansoni, has never been investigated. The above-mentioned hypothesis will be tested in three independents yet connected work packages as outlined below: Aim 1: To dissect the cellular and molecular components engaged at the interface of macrophage-apoptotic cell phagocytic synapse Aim 2: To examine to what extent in vivo phagocytosis of apoptotic cells with different cell identities differentially shapes macrophage function in the liver Aim 3: To investigate to what extent phagocytosis of selective apoptotic cells bymacrophages contributes to tolerance maintenance and/or reestablishment of homeostasis in the liver.Dissecting this unexplored macrophage-apoptotic cell interaction in the liver, where macrophages are highly phagocytic, might lead to development of more efficient macrophage cell therapies aimed at re-establishing liver homeostasis upon damage. Additionally, zooming into the identity of apoptotic cells, and investigating their impact on targeted phagocytic macrophages might not only pave the way for predicting the outcome of patient disease based on the identity of cells undergoing apoptosis, but might also reveal the etiology of some liver chronic diseases characterized by constant generation of apoptotic cells.

• DFG Programme: Research Grants