Figure 2.

Plasticity vs Heterogeneity in the Inflamed Murine Liver. (A) KCs are the main macrophage population in the homeostatic liver. They are the sentinel cells that can sense PAMPs from attacking pathogens and DAMPs from dying hepatocytes in the first stages of infection or liver tissue injury. KCs can also efferocytose cellular debris from dead hepatocytes (47). Sensing of PAMPs and/or DAMPs activates KCs to produce chemokines and cytokines to call in monocytes and neutrophils from circulation (7). Ly6C^hi monocytes can differentiate locally depending on the cues from their microenvironment into recruited-temporary macrophages or KCs. However, recruited KCs have not been observed in all settings (15). Alongside the recruited neutrophils, these recruited macrophage populations may produce cytokines at the site, and help with cleaning up the pathogens/cellular debris. The loss of resident KCs has been reported in many inflammatory settings (4, 15, 23–25, 32, 38, 39, 48) and may be caused by stress resulting from activation or from the increased metabolic load of ingested cellular debris. Recruited cells such as recruited-temporary macrophages and neutrophils help to clean up the KC debris (49) and, in case of pathogen-induced inflammation, to capture/eliminate pathogens and pathogen infected cells. Notably, neutrophils have limited lifespan in the tissues (49) and their debris is subsequently also cleaned up by hepatic macrophages (33). With cellular debris removed, hepatocytes have space to replenish their numbers through proliferation. Resident KC numbers are also replenished through their proliferation and/or engraftment of recruited KCs which subsequently acquire the resident KC phenotype (TIM4 expression). However, exactly how similar resident and recruited KCs are when the latter are generated in an inflammatory environment remains to be seen. (B) If the inflammatory insult is not resolved (e.g., in case of chronic infection, repeated injury or metabolic stress associated with increased lipid burden), the resolution phase is not reached and chronic inflammation develops. Increased KC death activates the niche cells (LSECs, HSCs and hepatocytes) to call in Ly6C^hi monocytes to replenish lost KCs (4, 23–25, 32). Continuous activation and/or tissue injury may lead to death of structural cells of the liver. The recruitment of cells from circulation is continuous. Recruited monocytes differentiate locally into KCs and/or recruited-temporary macrophages, depending on the cues from their microenvironment. For example, activated HSCs produce and deposit increased amounts of collagen, which leads to liver fibrosis. Monocytes recruited to fibrotic zones harbouring large numbers of activated stellate cells/fibroblasts differentiate into recruited-temporary macrophages expressing CD9⁺TREM2⁺ called hepatic LAMs/SAMs (4, 30, 32). As with acute injury/infection/inflammation, recruited KCs can acquire the TIM4-expression with time (4, 23) and the cycle continues. As in acute inflammation, how similar or distinct recruited and resident KCs are remains a matter of debate.