Macrophages Gobble Up Old Neutrophils to Heal Transplanted Livers New
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Scientists have revealed how a key receptor helps macrophages mitigate post-transplant liver injury by clearing old, inflammatory neutrophils.
Liver transplants save the lives of many people, but the procedure can result in severe complications. One of these common side effects is liver ischemia-reperfusion injury (LIRI), in which the oxygen-starved (ischemic) donor organ experiences a sudden rush of blood (reperfusion) that activates the recepient’s innate immune system, causing extreme inflammation.1 The subsequent tissue damage can negatively impact clinical outcomes and is often fatal.
In a study published today in Science Translational Medicineresearchers from the Tongji University have identified key factors that regulate LIRI and a potential therapeutic target that could improve clinical outcomes for liver transplant patients.2
Other researchers previously showed that macrophages and neutrophils, crucial cell types involved in innate immunity, play a major role in the inflammatory cascade leading to LIRI.3,4 In the present study, the researchers aimed to explore the role of macrophages and how they maintain homeostasis in the liver by resolving inflammation and tissue damage. Using spatial transcriptomics, single-cell RNA sequencing, and advanced intravital imaging techniques, the team peeked into the transplanted livers of living mice. Immediately after reperfusion, they observed neutrophils infiltrating the liver before they underwent senescence and cell death, which triggered the onset of LIRI.
Under normal conditions, macrophages travelled toward these old, dysfunctional neutrophils, surrounded and then engulfed them to remove them from the tissue—a process known as efferocytosis. By doing so, the macrophages halted necrosis, reduced inflammation, and helped the damaged tissue bounce back.
However, in some mice, macrophages failed to do their job properly; aged neutrophils accumulated in the injured tissue, leading to increased inflammation. Gene expression profiling of macrophages revealed that the culprit was MAS, a G protein-coupled receptor. Other researchers previously identified that MAS plays a role in warding off various diseases, but they did not fully understand its exact involvement in innate immunity and liver homeostasis.5
To uncover the role of this receptor in LIRI, the team generated More1 knockout mice and compared their disease progression with that of wild type mice. Without MAS, mice developed more severe liver injury: Macrophages failed to surround and consume the aged neutrophils, which accumulated and caused increased inflammation. MAS-deficient mice also displayed decreased expression of downstream signaling pathways, establishing a regulatory role for MAS in maintaining liver homeostasis.
The team also wanted to explore the clinical relevance of these results, so they examined biopsies of pre- and post-transplant human livers. Consistent with what they saw in mice, the researchers observed that high expression of MAS allowed macrophages to rapidly traffic to the senescent neutrophils and perform efficient efferocytosis, resolving LIRI.
Because MAS plays such a critical role in how macrophages respond to LIRI, the authors postulate that this receptor—or the downstream signaling pathways it regulates—could serve as a potential therapeutic target to improve clinical outcomes for liver transplant patients. LIRI also shares similarity with other conditions where tissues are starved of oxygen, including heart attacks, leading the team to suggest that their findings could also be broadly applicable.
