T‐Cell Immunoglobulin and Mucin Domain‐Containing Protein‐4 Is Critical for Kupffer Cell Homeostatic Function in the Activation and Resolution of Liver Ischemia Reperfusion Injury

Abstract

Background and Aims Liver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver‐resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T‐cell immunoglobulin and mucin domain‐containing protein‐4 (TIM‐4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model. Approach and Results Fluorescence‐activated cell sorting results showed that TIM‐4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti‐TIM‐4 antibody depleted TIM‐4+ macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b+ macrophages. To determine the KC‐specific function of TIM‐4, we reconstituted clodronate‐liposome–treated mice with exogenous wild‐type or TIM‐4‐deficient KCs at either 0 hour or 24 hours postreperfusion. TIM‐4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6 hours postreperfusion), but also impairment of the inflammation resolution (at 7 days postreperfusion). In vitro analysis revealed that TIM‐4 promoted KC efferocytosis to regulate their Toll‐like receptor response by up‐regulating IL‐10 and down‐regulating TNF‐α productions. Conclusions TIM‐4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.

Low MARCO Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma Following Liver Transplantation

“…Kupffer cells are liver-resident macrophages associated with proinflammatory reactions, ischemia-reperfusion, and immune reactions. 14 , 15 MARCO is typically expressed on restricted subpopulations of macrophages in peripheral immune organs. 16 We verified that MARCO expression was predominantly localized to Kupffer cells in HCC tissues, as determined by the colocalization of MARCO and CD68 using immunofluorescence.…”

Heterogeneity and Function of Kupffer Cells in Liver Injury

“…In adults, bone marrow monocytes also contribute to maintain KC pool when Em-KCs are insufficient to maintain it ( 13 ). Studies have demonstrated that when Em-KCs are depleted by clodronate liposomes (CLs) ( 14 , 15 ), diphtheria toxin ( 4 ), anti-TIM4 antibody ( 6 ) or high dose irradiation ( 16 ), monocytes are recruited and differentiate into KCs to replenish the vacancy. In patients received liver transplant, recipient macrophages are also emerged in transplanted livers ( 17 ).…”

“…But it should be noticed that these bone marrow monocyte-derived KCs (BM-KCs) are different from BMMs in injured liver. BM-KCs express KC markers (including CLEC4F, CLEC2, VSIG4, TIM4), while BMMs mainly highly express CCR2 and show no KC marker expressions ( 6 , 18 ).…”

“…In the new definition, mouse KCs are liver macrophages that specifically expressing CLEC4F regardless of origins ( 4 ). Besides, CLEC2 ( 5 ), TIM4 ( 6 ) and VSIG4 ( 7 ) are also recognized as mouse KC markers. Among them, VSIG4 has recently been reported to be conservative among mouse and human ( 7 ).…”

Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization

“…Hepatic macrophages play an important role in liver repair after acute liver injury, including hepatic I/R injury (2). Macrophage phenotype shift from a proinflammatory to a reparative phenotype in the inflammatory liver is crucial for liver repair following hepatic I/R injury (3)(4)(5)(6). However, the mechanisms by which the liver is repaired via macrophage differentiation remain to be elucidated.…”