Healthy subject monocytes Cirrhotic patient monocytes
Formation of LAP vesicles (in red and green) incorporating IgG (in gray) in the monocytes of cirrhotic patients but not in those of healthy subjects.
Cirrhosis is the terminal stage of liver disease. It is secondary to chronic aggression, whether of alcoholic, viral or metabolic origin. It affects 200,000 to 500,000 individuals in France and is responsible for 170,000 deaths per year in Europe. Ultimately, it leads to liver failure, the only curative treatment of which is transplantation. Inflammation plays a major role in the natural history of cirrhosis and also promotes the occurrence of complications such as “Acute on Chronic Liver Failure” (ACLF), a multi-organ failure associated with high mortality.
Collaborative work between the teams of Sophie Lotersztajn, Renato Monteiro, Loredana Saveanu, the anesthesia-resuscitation and hepatology departments of the Beaujon AP-HP hospital and a team from the Necker Institute for Sick Children made it possible to evidence that a new anti-inflammatory pathway called “Phagocytosis Associated with LC3 (LAP)” could constitute a target for new therapeutic approaches aimed at combating hepatic fibrosis and systemic inflammation, the source of many complications of cirrhosis. Their work, carried out on ex-vivo cultures of patient monocytes and murine models of the disease, indeed identifies LAP as a pathway that slows systemic and hepatic inflammation, and makes it possible to limit the progression of fibrosis. This anti-inflammatory mechanism is activated by circulating uncomplexed IgGs which bind specific receptors of immunoglobulins, the FcγRIIA receptors. Activation of LAP, already present in the early stages of liver fibrosis, persists in the cirrhosis stage but disappears when the disease progresses to ACLF. However, it can be restored when monocytes from ACLF patients are exposed to uncomplexed IgG fragments. These results suggest that a stimulation of LAP could constitute an interesting therapeutic track to prevent the progression of the disease and the occurrence of complications such as ACLF.
Source: JH Wan, E Weiss, S Ben Mkaddem et al. LC3-associated phagocytosis in myeloid cells is a gatekeeper against inflammation via inhibitory ITAM signaling during cirrhosis.
Science Translational Medicine 2020.