# Macrophage Heterogeneity in Liver Ischemia-Reperfusion Injury

## TL;DR

This study explores how different types of liver macrophages affect injury during liver ischemia and reperfusion.

## Contribution

The study identifies Gr-1+Trem-2+ infiltrating macrophages as protective and reveals an IL-1a/b-dependent pro-inflammatory role of Kupffer cells.

## Key findings

- Gr-1+CD11b+ infiltrating macrophages protect the liver from IRI through Trem-2 expression.
- Kupffer cell replacement with iMФs reduces IL-1a and IL-1b levels, decreasing inflammation.
- Blocking IL-1a or IL-1b reduces liver injury in a Kupffer cell-dependent manner.

## Abstract

Kupffer cells (KCs) are implicated in liver ischemia reperfusion injury (IRI). However, their precise roles vs. bone marrow–derived infiltrating macrophages (iMФs) remain controversial. In this study, we used Clec4F-tdTomato (DTR) mice to track KC-specific changes and assessed their function by DT-mediated depletion in the acute phase of liver IRI. We found that liver IR leads to substantial loss of embryonically derived Clec4F+TIM-4+ KCs, coinciding with pronounced infiltration of monocytes and neutrophils. A single dose of DT resulted in a complete replacement of Clec4F+ KCs with iMФs, leading to a temporally dynamic modulation of liver susceptibility to IRI: reduced at 24 hours but aggravated at 14 days following DT administration. The early liver protection was mediated by Gr-1+CD11b+ iMФs with high expression of Trem2. Anti-Gr-1 Abs or Trem-2 blockade abolished the cytoprotective phenotype and restored liver IRI. Differential gene expression analysis between KCs and iMФs revealed that KC Inflammatory responses were driven primarily by IL-1 family genes. KC replacement with iMФs resulted in significantly lower levels of IL-1a and IL-1b, gene expression in both sham and IR livers. Ab-mediated neutralization of either of these cytokines reduced liver IRI in KC-dependent manner. Together, these findings identify Gr-1+Trem-2+ iMФs as immunoregulatory players that protect livers from IRI and highlight an IL-1a/b dependent pro-inflammatory role of KCs.