Eliminating liver cells with apoptosis, in which cells are intended to die in a controlled manner, is probably a type of white blood cell function normally associated with immune responses to foreign particles.
The study, released as a peer-reviewed preprint in eLife , provides what the editors call solid evidence that neutrophils induce and kill liver cells undergoing apoptosis, a process the authors term “perforocytosis.” The findings may have implications for novel treatment approaches for the treatment of human autoimmune liver disease (AIL), which may result from neutrophil depletion.
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Billions of apoptotic cells are removed daily in adults by a group of immune cells called phagocytes. Neutrophils represent approximately 50-70% of the total white blood cell population in humans and are a type of phagocyte. However, unlike other phagocytes, they are thought to be excluded from apoptotic cells, as they promote inflammation that damages nearby healthy cells and tissues. Current findings now challenge that assumption.
“Although apoptotic cells have been well characterized, they are not often found in human specimens, possibly because they are so efficiently removed by phagocytes,” says co-lead author Luyang Cao, associate investigator in the Department of Neurosurgery, State Key Laboratory of Biotherapy and. Cancer Center, West China Hospital, Sichuan University, China. “This means that the specific phagocytes responsible for removing apoptotic cells remain unknown, and we do not know whether they are specific to different tissues of the body.”
To identify the phagocytes responsible for removing apoptotic cells in the liver, the team obtained cells from liver tissue of patients with tumors caused by hepatocellular carcinoma or hepatic hemangioma. They used two different staining techniques to confirm which cells in the sample were apoptotic.
In a total of 281 apoptotic liver cells from the livers of 32 patients, the team observed 22 neutrophils embedded in each cell. It has previously been suggested that a type of phagocyte called Kupffer cells was responsible for the clearance of apoptotic liver cells, but when the researchers looked for Kupffer cells in the samples, they were very few. They therefore hypothesized that neutrophils were the primary phagocyte for removing dead liver cells in a process they termed perforocytosis. This contrasts with the normal process of engulfing apoptotic cells that most other phagocytes use.
To confirm the mechanism by which neutrophils remove apoptotic liver cells, the team sought to visualize the process in mouse livers using intravital microscopy—a live imaging technique that allows biological processes to be observed in living organisms in real time. They labeled liver cells with a protein called annexin V and neutrophils with an anti-Ly6G antibody. Consistent with their findings in human samples, the team observed that neutrophils infiltrate and clean up dead liver cells in mice. The process was fast and rigorous, with dead cells completely digested in four to seven minutes.
“Our discovery that neutrophils accumulate and clear apoptotic liver cells helps solve some of the mysteries surrounding the apoptotic clearance process,” says co-corresponding author Hexige Saiyin, assistant professor at the State Key Laboratory of Genetic Engineering, School of Life Sciences. Fudan University, China.
Next, the team sought to investigate whether reducing the neutrophil population in mice affected the clearance of apoptotic liver cells. In samples of cells from the livers of neutrophil-depleted mice, the percentage of apoptotic cells was significantly higher than in normal mice—0.92% and 0.2%, respectively—suggesting that neutrophil depletion reduces clearance of apoptotic cells. They also observed the presence of other phagocytes in neutrophil-depleted mice, indicating a compensatory role of other phagocytes in the absence of neutrophils.
Defective clearance of apoptotic cells is often associated with autoimmune diseases such as AIL. In the neutrophil-depleted mice, the team saw an increase in autoantibodies – immune cells that mistakenly attack the body’s own healthy cells instead of foreign bodies such as viruses or bacteria. This increase was unaffected by antibiotic treatment and was observed only in neutrophil-depleted mice, not in other phagocyte-depleted mice. This indicates that neutrophil depletion is associated with impaired apoptotic liver cell clearance and, subsequently, production of autoantibodies that may lead to AIL disease. The team consolidated this finding by analyzing biopsy samples from human patients with AIL disease. Once again they found that, in each patient, neutrophil-mediated clearance of apoptotic cells was impaired.
The authors say more research is needed to better understand the process and significance of perforocytosis, as well as whether perforocytosis occurs in organs other than the liver. The next important step is how to apply this newly identified apoptotic clearance mechanism to the clinical treatment of AIL.
“Since failure to clear dead cells is linked to inflammatory and autoimmune diseases, further insights into the critical role neutrophils play in apoptotic clearance may have important implications for the treatment of these diseases. We have recently screened and identified several compounds that significantly increased neutrophil demonstrated excellent therapeutic values in perforocytosis and curing AIL in mouse models.” Senior author Jingsong Xu, former principal investigator of the Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University (current address: Dept. of Pharmacology, Lung and Vascular Center for Biology, University of Illinois, Chicago).
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