Inhibition of TIM-4 protects against cerebral ischaemia-reperfusion injury.

Lifang Zheng,Yongqian Huang,Xijia Wang,Chunlian Pan,Wei Chen,Wei Cheng,Xinghua Wang

doi:10.1111/jcmm.14754

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.

Highlights

As society continues to age, the incidence rate of ischaemic stroke has increased each year and tends to occur even more frequently in younger people.[1]
To further explore the potential contribution of the T cell immunoglobulin and mucin domain (TIM)‐4 blockade in middle cerebral artery occlusion (MCAO) mice, we examined the level of inflammatory cells and cytokines in each of the groups
Following cerebral I/R, inflammation induces the infiltration of peripheral inflammatory cells, microglia activation and the over‐generation of inflammatory mediators, which causes immune activation and secondary ischaemic injury to the brain tissue.[18]

Summary

| INTRODUCTION

As society continues to age, the incidence rate of ischaemic stroke has increased each year and tends to occur even more frequently in younger people.[1]. Cerebral reperfusion with a tissue plasminogen activator (tPA) or mechanical thrombectomy are the conventional therapeutic strategies used to treat acute ischaemic stroke within the appropriate time window.[3]. This effective time window for treatment is limited and been shown to be largely beneficial with number needed to treat 10 for intravenous throm‐ bolysis and only 2.6 for mechanical thrombectomy.[4]. Previous studies have implicated TIMs in the regulation of certain immune responses, including allergy, asthma, autoimmu‐ nity and transplant tolerance.[8,10]. Recent studies suggest that the TIM‐4 pathway plays an important role in IRI of the liver and kidney. Decreased TIM‐4 expression has been shown to alleviate IRI under hepatic ischaemic preconditions.[11]. The purpose of the present study was to detect the association between TIM‐4 and ischaemic stroke and the effect of TIM‐4 on ischaemic stroke

| MATERIALS AND METHODS

Findings

| DISCUSSION