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Insights into How Immune Cell Recruits Are Programmed To Defend the Liver

Researchers working with a mouse model have gained insights into the genetic and cellular factors that drive the transformation of circulating immune cells into Kupffer cells, part of the liver’s “special forces” of immune cells. This research focuses on a type of immune cell called the macrophage—derived from the Latin for “large” and “thing that devours”—that protects the body by engulfing pathogens and cellular debris. The Kupffer cell is a special type of macrophage residing in blood vessels within the liver. During early life, Kupffer cells develop in the liver, where they perform important functions lifelong, including clearing cell debris and toxins produced by gut bacteria, as well as playing a role in iron metabolism. Kupffer cells also play critical roles in some liver diseases and therefore could be targets for therapy, but little is known about the factors involved in the formation and maintenance of these unique liver defense cells.

Researchers aimed to address this knowledge gap by using a mouse model in which these cells can be experimentally depleted. They studied both female and male mice over a 2-week period, analyzing cells from blood and liver samples using techniques that show gene activation. In the first 12 hours after the mouse Kupffer cells were depleted, circulating monocytes (white blood cells in the immune system that can turn into more specialized immune cells as needed) had already started to colonize the liver. Within 24 hours of residing in the liver environment, the monocytes showed signs of a transformation, including activation of over half of the roughly 300 genes unique to Kupffer cells. A combination of sequential signals emanating from surrounding liver cells, including those lining blood vessels (called liver sinusoidal endothelial cells) and underlying liver cells called hepatocytes, were important for transforming the monocytes and maintaining their new identities as Kupffer-like cells. In the first step of the process, monocytes migrating to the liver interacted with sinusoidal cells that produced a protein called DLL4, setting off a cascade of gene activation needed to transform the cells. The second step involved signals such as transforming growth factor-beta and desmosterol released by the surrounding liver cells that further fine-tuned the gene activation program to resemble a Kupffer-like cell. These findings offer insights into the developmental program triggered in circulating immune cells—and within cells in the local tissue environment that sense a need to replace lost defenses—to form the Kupffer cells that protect the liver. Future directions for this research include plans to explore how Kupffer cells function in a disease context, such as a form of severe fatty liver disease called nonalcoholic steatohepatitis.

Sakai M, Troutman TD, Seidman JS,…Glass CK. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity 51: 655-670.e8, 2019.

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