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.