Tim4high expression identifies a Kupffer cell subset with enhanced catching proficiency

Background Kupffer cells (KCs) are tissue macrophages residing in liver sinusoids with critical functions to maintain liver homeostasis. Recent single-cell data in health and disease have expanded our understanding of the complexity of KCs and at least two subsets have been identified, however, a functional correlate of different KC subsets is largely unclear.

Methods Using a combination of intravital microscopy and spectral flow cytometry, we analyzed liver macrophages in healthy mice, mice with chronic liver injury and injury regression induced by CCl4 and human liver tissue.

Results We identified two subsets of F4/80+ KCs based on the expression of scavenger receptor Tim4. A subset of F4/80+Tim4high KCs with increased cell volume localized in the periportal region and efficiently filtered particulate targets out of the circulation. Flow cytometric analysis revealed expression of Tim4 by 70% within the KC population. Following chronic liver injury, we observed a marked loss of Tim4+ KCs correlating with a reduction of the KC filter function. Regression of liver damage led to normalization of transaminase levels and reversion of the histopathological phenotype, however, KC catching ability was still impaired as assessed by particle uptake. Importantly, the subset of Tim4high KCs was significantly lower during injury regression and catching was restricted to the remaining Tim4high KCs. Flow cytometry of human tissue revealed Tim4 expression by CD14+ KCs.

Conclusion Our results identify Tim4 as a marker indicating proficiency of KCs to filter particles. Chronic injury and regression are accompanied by loss of Tim4 and correlate with impaired liver clearance.

Publication History

Article published online:
26 January 2022