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.
