Dual Role of Hepatic Macrophages in the Establishment of the Echinococcus multilocularis Metacestode in Mice

Abstract

Echinococcus multilocularis larvae, predominantly located in the liver, cause a tumor-like parasitic disease, alveolar echinococcosis (AE), that is characterized by increased infiltration of various immune cells, including macrophages, around the lesion that produces an “immunosuppressive” microenvironment, favoring its persistent infection. However, the role of hepatic macrophages in the host defense against E. multilocularis infection remains poorly defined. Using human liver tissues from patients with AE and a hepatic experimental mouse model of E. multilocularis, we investigated the phenotype and function of hepatic macrophages during the parasite infection. In the present study, we found that a large number of CD68+ macrophages accumulated around the metacestode lesion in the liver of human AE samples and that both S100A9+ proinflammatory (M1 phenotype) and CD163+ anti-inflammatory (M2 phenotype) macrophages were significantly higher in close liver tissue (CLT) than in distant liver tissue (DLT), whereas M2 macrophages represent the dominant macrophage population. Furthermore, E. multilocularis-infected mice exhibited a massive increase in macrophage (F4/80+) infiltration in the liver as early as day 5, and the infiltrated macrophages were mainly monocyte-derived macrophages (CD11bhi F4/80int MoMFs) that preferentially differentiated into the M1 phenotype (iNOS+) at the early stage of E. multilocularis infection and then polarized to anti-inflammatory macrophages of the M2 phenotype (CD206+) at the chronic stage of infection. We further showed that elimination of macrophages by treatment of mice with clodronate-liposomes before E. multilocularis infection impaired worm expulsion and was accompanied by a reduction in liver fibrosis, yielding a high parasite burden. These results suggest that hepatic macrophages may play a dual role in the establishment and development of E. multilocularis metacestodes in which early larvae clearance is promoted by M1 macrophages while persistent metacestode infection is favored by M2 macrophages.

NSAID-Associated Small Intestinal Injury: An Overview From Animal Model Development to Pathogenesis, Treatment, and Prevention

“…It is not unusual for macrophages to show a dual role in inflammation. A study on alveolar echinococcosis revealed a dual role for hepatic macrophages, which researchers attributed to the differentiation of macrophages into different cell phenotypes at different stages ( Wang et al, 2020 ).…”

Vitamin D Deficiency During Development Permanently Alters Liver Cell Composition and Function

“…For instance, the infiltration and activation of macrophages is a key feature of endoplasmic reticulum stress-induced inflammation in liver injury, with VDR signaling regulating the inflammatory response in macrophages ( 47 ). We found that two distinct macrophage proportions, Cd163-positive, the anti-inflammatory (M2 phenotype) macrophages ( 48 ), and Ccr2-positive macrophages had distinct patterns of alteration in prenatal VDD offspring. Associations between the Ccr2-positive Kupffer cells (hepatic residential macrophage) and choline-deficient amino acid-defined diet-induced hepatic steatosis and fibrosis have been identified ( 49 , 50 ).…”

Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway

“…Parasitic infection was related to the macrophage polarization patterns [10][11][12][13]. Previous studies have found that numerous macrophages gathered around the lesion in AE patients, but the disease was still getting worse, and both M1 and M2 macrophages were signi cantly higher in close liver issue (CLT) than in distant liver tissue (DLT) from the lesion [12]. Pathogen infection modulated macrophages polarization through metabolic reprogramming by the PI3K/Akt/mTOR signaling pathway [14,15].…”

“…Macrophages coordinate proin ammatory and anti-in ammatory responses to infection and play an important role in the maintenance of cell homeostasis and repair. Parasitic infection was related to the macrophage polarization patterns [10][11][12][13]. Previous studies have found that numerous macrophages gathered around the lesion in AE patients, but the disease was still getting worse, and both M1 and M2 macrophages were signi cantly higher in close liver issue (CLT) than in distant liver tissue (DLT) from the lesion [12].…”

“…Pathogen infection modulated macrophages polarization through metabolic reprogramming by the PI3K/Akt/mTOR signaling pathway [14,15]. E. multilocularis infection changed glucose metabolism, macrophage polarization and PI3K/Akt/mTOR signaling pathways [11,12,16]. PI3K/Akt/mTOR signaling pathway promote M2 Polarization by increasing glucose uptake, intracellular ATP and changing glucose metabolism [17,18].Therefore, clarifying E. multilocularis protoscoleces (PSCs)enhance glycolysis to promote M2 macrophages through PI3K/Akt/mTOR signaling pathway may help us to understand the pathogenesis of AE.…”