Inhibition of TIM‐4 protects against cerebral ischaemia‐reperfusion injury

Abstract

TIM-4 plays an important role in ischaemia-reperfusion injury of liver and kidney; however, the effects of TIM-4 on cerebral ischaemia-reperfusion injury (IRI) are unknown. The purpose of the present study was to investigate the potential role of TIM-4 in experimental brain ischaemia-reperfusion injury. In this study, cerebral ischaemia reperfusion was induced by transient middle cerebral artery occlusion (MCAO) for 1 hour in C57/BL6 mice. The TIM-4 expression was detected in vivo or vitro by real-time quantitative polymerase chain reaction, Western blot and flow cytometric analysis. In vivo, the administration of anti-TIM-4 antibodies significantly suppressed apoptosis, inhibited inflammatory cells and enhanced anti-inflammatory responses. In vitro, activated microglia exhibited reduced cellular proliferation and induced IRI injury when co-cultured with neurons; these effects were inhibited by anti-TIM-4 antibody treatment. Similarly, microglia transfected with TIM-4 siRNA and stimulated by LPS + IFN-γ alleviated the TIM-4-mediated damage to neurons.Collectively, our data indicate that the inhibition of TIM-4 can improve the inflammatory response and exerts a protective effect in cerebral ischaemia-reperfusion injury. K E Y W O R D Scerebral ischaemia-reperfusion injury, co-culture, TIM-4

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

“…Perioperational administration of anti‐TIM‐4 Ab has been shown to protect livers, as well as kidneys and brains, from IRI, ( 18,19,22,23 ) which indicates a proinflammatory, rather than homeostatic, role of TIM‐4 in these organs. Interestingly, when we tested the Ab in our model, we found that it could either protect or damage livers depending on the time of the Ab administration: Liver IRI and inflammatory response were reduced when anti‐TIM‐4 was injected perioperationally at 2 hours, but enhanced when injected pre‐emptively at 48 hours, before the onset of liver ischemia (Fig.…”

“…In the current study, we addressed the question of whether TIM-4, as a macrophage efferocytosis coreceptor, plays an immune-regulatory role in the pathogenesis of liver IRI. Given that TIM-4 has been studied in several organ ischemia models (18,19,22,23) and anti-TIM-4 Abs were shown to inhibit tissue-inflammatory activation and protect from IR injury, (22,23) the question we clarified first was how the anti-TIM-4 Ab affected liver macrophages in vivo. We revealed the depleting nature of this Ab in mice and found that the repopulation kinetics of the KC niche determines the effect of anti-TIM-4 on liver IRI (Fig.…”

“…(20) Global TIM-4 deficiency and anti-TIM-4 antibody (Ab) treatment, however, protects livers, kidney, and brains from IRI, implicating its proinflammatory role. (18,9,22,23) In the current study, we focused on the KC-specific function of TIM-4 in not only the activation, but also the resolution stage of liver IRI. We initially characterized TIM-4 expression in livers in response to IR stress in both experimental and clinical hepatic tissue samples.…”

Histone Methylation Inhibitor DZNep Ameliorated the Renal Ischemia-Reperfusion Injury via Inhibiting TIM-1 Mediated T Cell Activation

“…The TIM-1-TIM-4 axis was suggested as a novel intervention target for IRI. Direct inhibition or induced depression of TIM-1 and TIM-4 protected against liver and cerebral IRI ( 25 – 29 ). Blocking the TIM-1-TIM-4 pathway by anti-TIM monoclonal antibody also diminished inflammation and improve apoptosis and survival in renal IRI ( 11 ).…”

Function and characteristics of TIM‑4 in immune regulation and disease (Review)

“…TIM-4 serves a different role in atherosclerosis (Table Ⅲ). At present, the main treatment of atherosclerosis is to reduce blood lipids, but in the face of the concurrence of lipid accumulation and inflammatory immunity, this method is not satisfactory in controlling disease progression or pathological state (117). Innate and adaptive immunity as well as apoptotic cell clearance serve a central role in the development of atherosclerosis and TIM-4 may affect this process.…”