Sustained macrophage alterations during chronic injury regression beget increased susceptibility to infections

The liver serves as the body’s central microbial filter preventing spread of blood-borne pathogens. To fulfil this critical task, the liver relies on a hub of immune surveillance, the liver sinusoids which contain the most abundant population of tissue resident macrophages, the Kupffer cells (KCs). In homeostasis, KCs filter>90% of disseminated bacteria within minutes from the blood. In contrast, during chronic liver injury and fibrosis KCs dramatically change their phenotype, lose their identity and their function. Furthermore, monocytes invade the liver with an individual functional profile and form KC-like syncytia that compensate for loss of KC function on the level of sinusoids. However, it is unclear how the liver macrophage compartment responds to injury regression which is seen in patients with chronic liver diseases. Using a mouse model of chronic toxicity and regression of hepatic injury, numerous monocyte and macrophage linage tracing tools, intravital microscopy and multiplex flow cytometry we investigated the liver macrophage compartment during injury regression. Liver architecture and liver damage completely normalized in regression. Surprisingly, we found sustained alterations macrophage compartment that included differences in KC identity molecules such as CRIg and TIM-4. Functionally, bacterial capture was reduced in regression compared to control mice. Flow cytometric profiling revealed an emerging population of monocyte-derived KCs. Furthermore, we found a novel macrophage subset expressing the markers MerTK, CD68, CD86 and PD-L1. Our results demonstrate sustained alteration of the liver macrophage compartment during injury regression, favoring injury repair over antimicrobial responses thus leaving the host vulnerable to infections.

 

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Publication History

Article published online:
23 January 2024