Macrophage Heterogeneity in Liver Ischemia-Reperfusion Injury

Area of Science:

• Immunology
• Hepatology
• Cell Biology

Background:

• Kupffer cells (KCs) and infiltrating macrophages (iMФs) have debated roles in liver ischemia reperfusion injury (IRI).
• Understanding their distinct functions is crucial for developing targeted therapies for liver injury.

Purpose of the Study:

• To investigate the specific roles of KCs versus iMФs in the acute phase of liver IRI.
• To elucidate the mechanisms underlying the protective or detrimental effects of these immune cells.

Main Methods:

• Utilized Clec4F-tdTomato (DTR) reporter mice for tracking and depleting KCs via diphtheria toxin (DT).
• Assessed liver susceptibility to IRI at different time points after KC depletion.
• Analyzed macrophage populations (Gr-1⁺CD11b⁺ iMФs) and their expression of Trem2.
• Performed differential gene expression analysis between KCs and iMФs, focusing on IL-1 family cytokines.

Main Results:

• Liver IR caused a loss of KCs and infiltration of monocytes/neutrophils.
• DT-mediated KC depletion led to iMФ replacement, initially protecting the liver at 24 hours but worsening injury at 14 days.
• Early protection was mediated by Gr-1⁺CD11b⁺ iMФs expressing Trem2; blocking these abrogated protection.
• KCs exhibited higher inflammatory responses driven by IL-1 family genes (IL-1a/b) compared to iMФs.
• Neutralizing IL-1a/b reduced liver IRI in a KC-dependent manner.

Conclusions:

• Gr-1⁺Trem-2⁺ iMФs act as key immunoregulatory cells providing early protection against liver IRI.
• KCs play a pro-inflammatory role in liver IRI, primarily through IL-1a/b signaling.
• Targeting iMФs or inhibiting KC-derived IL-1a/b may offer therapeutic strategies for liver IRI.