MACtivate · Understanding hepatic macrophage activation by microbes and microbial components in vivo
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-04-01 → 2023-03-31
- EU contribution
- €166,320
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Understanding hepatic macrophage activation by microbes and microbial components in vivo
Macrophages are specialized immune cells and are present in virtually all organs of the body. There, these cells carry out different organ-specific functions but also play an important role in defending the immune system. In the liver the tissue resident macrophages are termed Kupffer cells (KCs). These cells reside in the blood vessel of the liver called sinusoids in close contact with endothelial and stellate cells and are thus ideally positioned to recognize, capture and eliminate microbes and microbial components reaching the liver. Although, these cells have been proposed to exert critical function in systemic immune surveillance, little is known about the cellular and molecular mechanisms underpinning KC responses to microbial insult. During inflammation resident macrophages are often lost and monocyte-derived cells are recruited to the site of inflammation where these cells contribute to anti-microbial immunity and tissue repair. Recruited monocytes can differentiate into macrophages and display similar surface markers and expression profiles compared to resident macs which in the past has hampered the unambiguous identification of the different macrophage populations and thus our understanding of their specific functions during inflammation. However, the KC-specific markers identified recently now allow to ambiguously discriminate between the different macrophages present in the liver after microbe-induced inflammation. Focusing on KCs we have determined their fate, specific responses and functions during microbial insult (WP1). Preliminary data have shown that mice lacking a negative regulator of the inflammatory response specifically in KCs develop excessive systemic inflammation and show increased mortality upon exposure to the microbial component LPS. Here, we have investigated the cellular and molecular processes leading to severe inflammation in these mice (WP2). Ultimately, we have provided novel insight into the crosstalk between KCs and their cellular environment in the liver during microbial inflammation (WP3).
Data: CORDIS, © European Union
Project objective
Despite playing essential roles in immunity against microbes, the cellular and molecular mechanisms underpinning macrophage (mac) responses to microbial insults remain incompletely understood. In the liver, Kupffer cells (KCs) the tissue-resident macs, reside in the bloodstream of the liver sinusoids and are thus ideally positioned to recognize and phagocytize microbes and microbe-derived components critically contributing to systemic immune surveillance. In addition, KCs are thought to play central roles in maintaining tolerance for example to gut microbiota and/or their products which reach the liver through the portal vein. Upon inflammation/infection, monocytes are also often recruited to liver which, in addition to KCs, participate in immune defence and tissue repair and can differentiate into recruited macs (rMacs). Due to similar expression profiles and functions it has not been possible to unambiguously discriminate between resident KCs and rMacs in the past hampering our understanding of the processes underlying hepatic mac activation by microbes and microbial components. By combining my expertise in host-microbe interactions with the expertise of the host lab in myeloid cell biology, here, I aim to dissect the mac responses to microbial insult in the liver. To achieve this, I will use KC-specific mouse models and human liver organoids combined with novel single cell technologies, with a focus on mac fate, activation profile and tissue context. My preliminary data demonstrate that systemic microbial insult leads to significant heterogeneity within the hepatic mac pool and hence I hypothesize that individual populations may become differentially activated in order to effectively clear microbes and microbial components from the liver. Understanding the processes underpinning mac activation by microbes/microbial products may allow us to manipulate these responses with the ultimate goal of improving patient outcomes.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union