M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes

Abstract

Acute injury in the setting of liver fibrosis is an interesting and still unsettled issue. Most recently, several prominent studies have indicated the favourable effects of liver fibrosis against acute insults. Nevertheless, the underlying mechanisms governing this hepatoprotection remain obscure. In the present study, we hypothesized that macrophages and their M1/M2 activation critically involve in the hepatoprotection conferred by liver fibrosis. Our findings demonstrated that liver fibrosis manifested a beneficial role for host survival and apoptosis resistance. Hepatoprotection in the fibrotic liver was tightly related to innate immune tolerance. Macrophages undertook crucial but divergent roles in homeostasis and fibrosis: depleting macrophages in control mice protected from acute insult; conversely, depleting macrophages in fibrotic liver weakened the hepatoprotection and gave rise to exacerbated liver injury upon insult. The contradictory effects of macrophages can be ascribed, to a great extent, to the heterogeneity in macrophage activation. Macrophages in fibrotic mice exhibited M2-preponderant activation, which was not the case in acutely injured liver. Adoptive transfer of M2-like macrophages conferred control mice conspicuous protection against insult. In vitro, M2-polarized macrophages protected hepatocytes against apoptosis. Together, M2-like macrophages in fibrotic liver exert the protective effects against lethal insults through conferring apoptosis resistance to hepatocytes.

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair

“…In other words, the overall macrophage phenotype at the injured liver changes as the injury progresses and wound healing takes place, and perivascular cells or their progeny are involved in this change. In line with this, a hepatoprotective effect of fibrosis has been linked to alternatively activated macrophages (M2-like macrophages) that develop in the fibrotic liver and protect hepatocytes from apoptosis [104]. The ability of activated HSCs to shift macrophage polarization toward an M2-like phenotype, however, is detrimental in cases of hepatic cancer, as the immunosuppressive actions of these macrophages hinder the elimination of cancer cells by the immune system which contributes to poor prognosis [105].…”

The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

“…Furthermore, IL-4-stimulated macrophages showed an increased production of anti-inflammatory cytokines (IL-10 and IL-1R antagonist) in conjunction with a reduced expression of proinflammatory/M1-like cytokines (IL-1, TNFα, IL-6, IL-12, and MIP1α), an essential step to dampen inflammation. Furthermore, in animal models of both acute (42,43) and chronic liver diseases (44), the ability of M2 macrophages to blunt inflammation also relies on the stimulation of apoptosis in M1 macrophages via a IL-10-mediated mechanism, which affects the balance between the anti-and pro-apoptotic proteins Bax and Bcl-2. In addition to the immunomodulatory functions, M2 macrophages are pivotal players in tissue regeneration and repair given their contribution to angiogenesis and ECM remodeling (45).…”

Phenotypic switch of human and mouse macrophages and resultant effects on apoptosis resistance in hepatocytes

“…Primary mouse macrophages (see Figure 1) were isolated from the livers of mice by pronase (Roche Diagnostics GmbH, Mannheim, Germany) and collagenase (Sigma-Aldrich, St. Louis, MO, USA) digestion followed by differential centrifugation using our previously reported method. 10 Isolated macrophages (nonpolarized M0 macrophages) were stimulated with mouse recombinant IFN-c (100 U/ml, PeproTech, Rocky Hill, USA) or IL-4 (10 ng/ml, PeproTech). Twenty-four h later, parts of M(IFN-c) or M(IL-4) macrophages were exposed to IL-4 or IFN-c stimulation, respectively, for another 24 h. In other words, mouse macrophages were divided into five groups: M0, M(IFN-c), M(IFN-c!IL-4), M(IL-4), and M(IL-4!IFN-c).…”

“…The phenotype of the subsets was identified through qRT-PCR analysis for gene signatures of representative markers. 10,[22][23][24][25] In addition, supernatants from all subsets were collected for conditioned medium experiment.…”

“…Considering that currently there is no canonical mouse model of ACLF, researchers utilize mice subjected to acute insult in the context of hepatic fibrosis to simulate the development of ACLF. In this regard, hepatic fibrosis induced by carbon tetrachloride (CCl 4 ), bile duct ligation (BDL), and thioacetamide (TAA) has been demonstrated to exert the hepatoprotective effects against various acute insults including D-galactosamine/LPS (D-GalN/LPS), 8 acetaminophen (APAP), 9 CCl 4 , 10 and TNF-a/Fas-induced apoptosis. [11][12][13] At the cellular level, innate immune cells, especially macrophages, are considered as the major contributor to injury resistance in the fibrosis setting.…”