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

Abstract

Acute-on-chronic liver failure (ACLF) carries a significant burden on critical care services and health care resources. However, the exact pathogenesis of ACLF remains to be elucidated, and novel treatments are desperately required. In our previous work, we utilized mice subjected to acute insult in the context of hepatic fibrosis to simulate the development of ACLF and documented the favorable hepatoprotection conferred by M2-like macrophages in vivo and in vitro. In the present study, we focused on the phenotypic switch of human and mouse macrophages and assessed the effects of this switch on apoptosis resistance in hepatocytes. For this purpose, human and mouse macrophages were isolated and polarized into M0, M(IFN-γ), M(IFN-γ→IL-4), M(IL-4) or M(IL-4→IFN-γ) subsets. Conditioned media (CM) from these subsets were applied to human and mouse hepatocytes followed by apoptosis induction. Cell apoptosis was evaluated by immunostaining for cleaved caspase-3. As a result, M(IFN-γ) or M(IL-4) macrophages switched their phenotype into M(IFN-γ→IL-4) or M(IL-4→IFN-γ) through reprogramming with IL-4 or IFN-γ, respectively. Importantly, hepatocytes pre-treated with M(IFN-γ→IL-4) CMs exhibited much weaker expression of cleaved caspase-3, compared to those pre-treated with M(IFN-γ) CM, and vice versa. Together, phenotypic switch of macrophages toward M(IL-4) phenotype confers hepatocytes enhanced resistance to apoptosis.

M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis

“…In the past few years, we have focused on elucidating this issue from the viewpoint of M1/M2 macrophage activation. Our major findings are as follows: firstly, hepatic fibrosis protects mice against diverse lethal insults; secondly, the hepatoprotection conferred by hepatic fibrosis can be attributed to M2-like activation of macrophages; and finally, M2-like macrophages derived from mouse livers and human PBMCs protect hepatocytes against apoptosis [3][4][5] .…”

Some Immunological and Genetic Aspects of the Development of Traumatic Osteomyelitis: a Review of the Literature

“…High production of IL-10 inhibits liver fibrosis. Short-term treatment of patients with chronic hepatitis C with recombinant IL-10 led to a decrease in inflammation and liver fibrosis; however, treatment of patients with liver fibrosis with IL-10 for a year led to an increase in the serum level of viral RNA, confirming that IL-10 not only suppresses fibrogenesis but also increases viremia as a result of a decrease in the number of HCV-specific CD4+ and CD8+ IFN-y-secreting T cells and polarization of the immune response towards the Th2 type [68,69].…”

Extracellular vesicles derived from M2‐like macrophages alleviate acute lung injury in a miR‐709‐mediated manner

“…M1φ are primarily involved in proinflammatory processes, and are a major source of numerous cytokines including IL‐6, TNF‐α and IL‐1β, which contribute to tissue damage following infections (Wang et al., 2020 ). In contrast, M2φ have been shown to play anti‐inflammatory and tissue repair roles in mouse models of acute liver failure, acute kidney injury, colitis and ALI (Bai et al., 2021 ; Feng et al., 2023 ; Lin et al., 2014 ; Song et al., 2019 ; Tang et al., 2020 ), partly by inhibiting NLRP3 inflammasome activation (Bai et al., 2017 ; Bai et al., 2018 ; Bai et al., 2019 ). However, practical applications of macrophage‐oriented cell therapy in vivo face several limitations.…”