High macrophage activities are associated with advanced periductal fibrosis in chronic Opisthorchis viverrini infection

Abstract

Liver fluke infection caused by Opisthorchis viverrini induces several hepatobiliary conditions including advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), but >25% of the infected population develops APF and 1% develop CCA. The innate immune response is the first line of defense, and macrophages are critical regulators of fibrosis. We hypothesized that macrophages from infected individuals have different capacities to either promote or suppress periductal fibrosis. We compared phagocytic activities of macrophages of healthy individuals and O. viverrini-infected individuals ±APF, and found that macrophages from infected individuals with APF ingested significantly higher numbers of beads compared with healthy controls and O. viverrini-infected individuals without APF. To further investigate proteolytic activity, we monitored real-time phagosomal proteolysis of beads conjugated to DQ BODIPY-BSA using live-cell imaging. We show that macrophages from O. viverrini-infected individuals with APF also have elevated phagosomal proteolysis activity, which is consistent with their increased phagocytic activity. Additionally, stimulated ROS production by blood monocytes was higher in individuals with APF compared with healthy controls and infected individuals without APF. These results suggest that during O. viverrini infection, macrophages with high phagocytic and proteolytic activities together with elevated ROS production, are the phenotypes that can promote tissue damage, which results in periductal fibrosis.

Unraveling the relationship among inflammatory responses, oxidative damage, and host susceptibility to Opisthorchis viverrini infection: A comparative analysis in animal models

“…A significantly higher number of macrophages in the lamina propria have been reported during the early stages of O. viverrini infection in hamsters [ 12 ]. In this stage, macrophages primarily contribute to producing free radicals, which act as cytotoxic effectors, promote tissue injury, and damage DNA [ 38 – 40 ]. Our data further explains the relationship between free radical production and DNA damage in susceptible and non-susceptible animals.…”

Inflammatory cell responses in biliary mucosa during Opisthorchis viverrini infection: Insights into susceptibility differences among hosts

“…Macrophages were detected among the granulomatous tissue, consistent with previous studies ( Sripa and Kaewkes, 2000a ; Lvova et al ., 2012 ). During O. viverrini infection, macrophages with high phagocytic and proteolytic activities, along with elevated ROS production, can promote tissue damage leading to PDF ( Salao et al ., 2019 ). IL-4 and IL-13, based on Th2 response, stimulate macrophages to become alternatively activated macrophages (AAMs) or M2, which secrete mediators with a slow-killing effect on helminths ( Yasuda and Nakanishi, 2018 ).…”

N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice

“…At least, the M1/M2 ratio was higher in the older group and its correlation with collagen deposition suggests that inflammation is involved in the aging process and fibrosis development ( Figure 3 ). M1 can switch to M2 [ 38 ], and high levels of M2 were expressed in NAC treatment group suggesting the anti-inflammatory effect of NAC on anti-fibrosis during the process of physiological aging and the possible mechanism underlying M2 polarization ( Figures 3 and 4 ). However, some researchers indicated that continuous activation of M2 macrophages may impair tissue regeneration and function by promoting fibrosis [ 39 , 40 ].…”