TIM-4 is critical for KC homeostatic function in the activation and resolution of liver ischemia reperfusion injury.

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 TIM-4, in both the activation and resolution of IRI in a murine liver partial warm ischemia model. FACS results showed that TIM-4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs) in IR-livers. Anti-TIM-4 Ab 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 KC-specific function of TIM-4, we reconstituted clodronate liposome-treated mice with exogenous WT or TIM-4 deficient KCs at either 0h or 24h post reperfusion. TIM-4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6h post reperfusion) but also impairment of the inflammation resolution (at 7 days post reperfusion). In vitro analysis revealed that TIM-4 promoted KC efferocytosis to regulate their TLR response by upregulating IL-10 and downregulating TNF-α productions. In conclusion, TIM-4 is critical for KC homeostatic function in both the activation and resolution of liver IRI via efferocytosis.