Macrophage Heterogeneity in Liver Ischemia-Reperfusion Injury

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.