Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis.

In adults, liver-resident macrophages, or Kupffer cells (KCs), reside in the sinusoids and sterilize circulating blood by capturing rapidly flowing microbes. We developed quantitative intravital imaging of 1-day-old mice combined with transcriptomics, genetic manipulation, and in vivo infection assays to interrogate increased susceptibility of newborns to bloodstream infections. Whereas 1-day-old KCs were better at catching Escherichia coli in vitro, we uncovered a critical 1-week window postpartum when KCs have limited access to blood and must translocate from liver parenchyma into the sinusoids. KC migration was independent of the microbiome but depended on macrophage migration inhibitory factor, its receptor CD74, and the adhesion molecule CD44. On the basis of our findings, we propose a model of progenitor macrophage seeding of the liver sinusoids via a reverse transmigration process from liver parenchyma. These results also illustrate the importance of developing newborn mouse models to understand newborn immunity and disease. Editor's summary: Newborns are particularly vulnerable to bloodstream bacterial infections that can lead to meningitis, but the mechanisms underlying this susceptibility are not fully understood. Using real-time intravital microscopy of neonatal mice, Araujo David et al. found that relocalization of Kupffer cells (KCs) from the liver parenchyma into sinusoids during the first week of life coincides with improved clearance of bloodstream bacteria. KC migration into liver sinusoids required macrophage migration inhibitory factor and its receptor CD74 but was independent of the microbiome. These findings demonstrate that delayed KC seeding of the liver sinusoids postnatally may underlie the increased susceptibility to bloodstream infections in newborns. —Claire Olingy [ABSTRACT FROM AUTHOR]