Kupffer cell–like syncytia replenish resident macrophage function in the fibrotic liver

Kupffer cells (KCs) are localized in liver sinusoids but extend pseudopods to parenchymal cells to maintain their identity and serve as the body’s central bacterial filter. Liver cirrhosis drastically alters vascular architecture, but how KCs adapt is unclear. We used a mouse model of liver fibrosis and human tissue to examine immune adaptation. Fibrosis forced KCs to lose contact with parenchymal cells, down-regulating “KC identity,” which rendered them incapable of clearing bacteria. Commensals stimulated the recruitment of monocytes through CD44 to a spatially distinct vascular compartment. There, recruited monocytes formed large aggregates of multinucleated cells (syncytia) that expressed phenotypical KC markers and displayed enhanced bacterial capture ability. Syncytia formed via CD36 and were observed in human cirrhosis as a possible antimicrobial defense that evolved with fibrosis. Description Editor’s summary Kupffer cells (KCs) are specialized macrophages in the liver sinusoids that filter bacteria in the bloodstream. Liver fibrosis and cirrhosis, a common pathology of chronic liver disease, leads to the redistribution of blood flow from the sinusoids to collateral vessels. Using a mouse model of hepatic fibrosis, Peiseler et al. report that remodeling of the liver causes KCs to lose contact with surrounding cells and lose their distinct cellular identity (see the Perspective by Louwe and Guilliams). The liver still maintains its bacterial filtration function because the presence of a microbiome helps to recruit monocytes to large intrahepatic vessels, where they fuse into large cell aggregates that exhibit a KC-like phenotype. These KC-like syncytia show enhanced bacterial capture capacity and are present in cirrhotic livers from patients with various chronic liver diseases. —Seth Thomas Scanlon Fibrosis-associated loss of Kupffer cells is compensated by bacteria-filtering monocyte syncytia in the liver. INTRODUCTION The local environment is critical for establishing the phenotype of macrophages within a given organ. In the liver, resident macrophages reach out of the sinusoids to receive instructive cues in a niche composed of hepatocytes, endothelial cells, and stellate cells. These cues activate specific transcription factors, which endow these macrophages with Kupffer cell (KC) “identity. ” In the sinusoids, KCs perform the critical function of capturing pathogens from the blood by means of specialized receptors, including the complement receptor CRIg. Liver fibrosis and cirrhosis is the common end-stage of various chronic liver diseases, leading to substantial morbidity and mortality in affected individuals. Despite different etiologies, progression is similar, with hepatocyte death and collagen deposition around sinusoids, resulting in the redistribution of blood flow to new and expanded intrahepatic and extrahepatic collateral vessels. RATIONALE It remains unclear how fibrotic remodeling of the niche environment affects the KC compartment. In this study, we used various lineage-tracing models and intravital microscopy to visualize, track, and functionally assess monocytes and KCs in the fibrotic liver environment. RESULTS Using the most common mouse model of liver fibrosis—carbon tetrachloride toxicity—we observed profound architectural changes in the liver. This remodeling included a massive increase in collateral vessels and collagen deposition around the sinusoids, which caused KCs to lose contact with their surrounding environment. This, in turn, led to the down-regulation of key transcription factors and membrane proteins such as CLEC4F, CRIg, and TIM-4, which collectively determine KC identity. Although these changes resulted in impaired KC function, the liver continued to act as a major filter of blood-borne bacteria despite the loss of KC identity. An abundance of monocytes were recruited, and these cells primarily adhered to large intrahepatic vessels through CD44 owing to increased endothelial cell adhesivity driven by intestinal microbiota. Monocytes formed large clusters within the collateral vessels and began to express KC markers. These monocytes made up a spectrum of structures ranging from clusters of individual cells to fused multinucleated giant cells that collectively appeared as KC-like syncytia. Although individual KCs could not catch bacteria flowing within larger vessels, KC-like syncytia were able to capture high numbers of circulating bacteria. Using transcriptomic analysis, we identified CD36 as the key molecule underlying syncytial fusion and reduced susceptibility to infection. CRIg-expresssing intravascular macrophage syncytia were also found in human cirrhosis of different etiology. CONCLUSION Loss of contact with parenchymal cells in the fibrotic niche leads sinusoid-resident KCs to lose identity and function. Because KC replenishment in rarefied sinusoids would serve little purpose, monocytes follow the formation of collateral vessels that bypass sinusoids, where they form KC-like syncytia that have the capacity to capture bacteria from the bloodstream. Thus, KC maladaptation within an altered fibrotic niche environment is rescued by monocytes forming KC-like syncytia to capture bacteria. These cell structures may play a critical evolutionary role that allows mammals to withstand severe chronic insults in the liver. Kupffer cell adaptation in fibrotic liver disease. In healthy livers, KCs reside in sinusoids and rapidly capture blood-borne pathogens. In liver fibrosis, sinusoids are rarefied, leading to redistributed circulation through high-flow collateral vessels. KCs consequently lose their identity and function. Monocytes then seed larger vessels and form KC-like syncytia with the heightened capacity to capture bacteria, providing a rescue adaptation to the fibrosis-induced loss of KCs.