Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury

Abstract

The role of macrophages in the pathogenesis of acetaminophen (APAP)-induced liver injury remains controversial, as it has been demonstrated that these cells display pro-toxicant and hepato-protective functions. This controversy may stem from the heterogeneity and/or plasticity of macrophages and the difficulty in distinguishing and differentially studying subpopulations of macrophages in the liver. In the present study, using flow cytometric analysis and fluorescence-labeled antibodies against specific cell surface macrophage markers, we were able to, for the first time, identify an APAP-induced macrophage (IM) population distinct from resident Kupffer cells. The data demonstrated that the IMs were derived from circulating monocytes that infiltrated the liver following APAP-induced liver injury. The IMs exhibited a phenotype consistent with that of alternatively activated macrophages and demonstrated the ability to phagocytize apoptotic cells and induce apoptosis of neutrophils. Furthermore, in the absence of the IMs, the resolution of hepatic damage following APAP-induced hepatotoxicity was delayed in CCR2(-/-) mice compared with wild-type mice. These findings likely contribute to the role of the IMs in the processes of tissue repair, including counteracting inflammation and promoting angiogenesis. The present study also demonstrated the ability of separating populations of macrophages and delineating distinct functions of each group in future studies of inflammatory disease in the liver and other tissues.

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

“…F4/80 hi CD11B intermediate macrophages predominated in the control (uninjured) liver and represent the resident Kupffer cell population (22) (Fig. 2C).…”

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…The depletion of CD11b + Gr1 + myeloid cells dramatically aggravated the acute liver injury comparing with secreted IL-1α expression alone, suggesting that the CD11b + Gr1 + myeloid cells play a protective role during acute liver injury and may be a negative feedback induced by secreted IL-1α. Monocytes could be recruited from the blood during acute liver injury and proliferate extensively in the liver [19][20][21]. In order to determine whether secreted IL-1α could enhance the proliferation of CD11b + Gr1 + myeloid cells during acute liver injury, we injected the mice i.p.…”

“…Monocytes could be recruited from the blood during acute liver injury and proliferate extensively in the liver [19][20][21]. In order to determine whether secreted IL-1α could enhance the proliferation of CD11b + Gr1 + myeloid cells during acute liver injury, we injected the mice i.p.…”

“…Most of these infiltrating monocytes may differentiate to M1 macrophages contributing to liver inflammation [21,22]. However, recent studies challenged this notion by showing local and intrahepatic infiltrating macrophages might be polarized toward M2 phenotype and elicited a protective role by promoting inflammation resolution and tissue repair [19,23,24]. CD11b + Gr1 + myeloid cells have been defined as myeloid derived suppressor cells (MDSCs) and suppress immune responses in many tumor models [25,26].…”

“…On the other hand, increasing evidences showed that hepatic macrophages (kupffer cells) are important players in the propagation of acute liver damage. During acute liver injury the intrahepatic macrophages massively expanded because of the influx of peripheral monocytes rather than the proliferation of the tissue-resident macrophages [19][20][21]. Most of these infiltrating monocytes may differentiate to M1 macrophages contributing to liver inflammation [21,22].…”