Anti-Interleukin-16 Neutralizing Antibody Treatment Alleviates Sepsis-Induced Cardiac Injury and Dysfunction via the Nuclear Factor Erythroid-2 Related Factor 2 Pathway in Mice

Jianwei Zhang,Changxing Hu,Zhishan Liang,Zicong Yang,Ling Liu,Mengjie Wang,Lei Shi,Qingwei Ji,Chao Chang,Marina Politi Okoshi

doi:10.1155/2021/6616422

Abstract

Several interleukin (IL) members have been reported to participate in sepsis. In this study, the effects of IL-16 on sepsis-induced cardiac injury and dysfunction were examined, and the related mechanisms were detected. IL-16 expression in septic mice was first measured, and the results showed that both cardiac and serum IL-16 expression levels were increased in mice with sepsis induced by LPS or cecal ligation and puncture (CLP) compared with control mice. Then, IL-16 was neutralized, and the effects on lipopolysaccharide- (LPS-) induced cardiac injury were detected. The results showed that an anti-IL-16 neutralizing antibody (nAb) significantly reduced mortality and increased serum lactate dehydrogenase (LDH), creatine kinase myocardial bound (CK-MB), and cardiac troponin T (cTnT) levels while improving cardiac function in mice with LPS-induced sepsis. Neutralization of IL-16 also increased the activation of antioxidant pathways and the expression of antioxidant factors in septic mice while decreasing the activation of prooxidant pathways and the expression of prooxidants. Treatment with the anti-IL-16 nAb increased mitochondrial apoptosis-inducing factor (AIF) expression, decreased nuclear AIF and cleaved poly-ADP-ribose polymerase (PARP) expression, and decreased TUNEL-positive cell percentages in LPS-treated mice. Additionally, treatment with CPUY192018, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway, significantly increased mortality and reversed the above effects in mice treated with LPS and the anti-IL-16 nAb. Our results showed that the anti-IL-16 nAb regulates oxidative stress through the Nrf2 pathway and participates in the regulation of cardiac injury in septic mice. Neutralization of IL-16 may be a beneficial strategy for the prevention of cardiac injury and dysfunction in sepsis patients.

Highlights

Sepsis is a complex set of clinical syndromes that can lead to the failure of multiple vital organs
We examined the effect of IL-16 on sepsisinduced cardiac injury and dysfunction and focused on oxidative stress to elucidate the possible mechanisms
For the first time, that both cardiac and serum IL-16 expression levels were elevated in both LPS- and cecal ligation and puncture (CLP)-induced mouse sepsis models

Summary

Introduction

Sepsis is a complex set of clinical syndromes that can lead to the failure of multiple vital organs. In an earlier study, circulating IL-26 levels were found to be significantly elevated in sepsis patients and to be correlated with severity and survival, and peritoneal inflammatory responses were found to be increased in septic mice treated. In mice with cecal ligation and puncture- (CLP-) induced sepsis, treatment with IL-34 has been found to significantly reduce macrophage infiltration, protect against organ injury, and improve survival, while neutralization of IL-34 exerts the opposite effects [7]. Serum IL-38 levels are elevated in both septic adults and septic children, and neutralization of IL-38 significantly amplifies inflammatory responses and reduces survival in mice with both lipopolysaccharide- (LPS-) and CLP-induced sepsis [8]. We determined whether IL-16 participates in sepsis-induced cardiac injury and dysfunction through the regulation of oxidative stress

Experimental Materials and Methods

Part 1

Results

Discussion