The inhibitor of interleukin-3 receptor protects against sepsis in a rat model of cecal ligation and puncture

Juntao Hu; Zhanhong Tang; Jing Xu; Weiwei Ge; Qiaohua Hu; Fengliang He; Guanghui Zheng; Longyuan Jiang; Zhengfei Yang; Wanchun Tang

doi:10.1016/j.molimm.2019.03.002

The inhibitor of interleukin-3 receptor protects against sepsis in a rat model of cecal ligation and puncture

Mol Immunol. 2019 May:109:71-80. doi: 10.1016/j.molimm.2019.03.002. Epub 2019 Mar 11.

Authors

Juntao Hu¹, Zhanhong Tang², Jing Xu³, Weiwei Ge⁴, Qiaohua Hu⁵, Fengliang He⁴, Guanghui Zheng⁵, Longyuan Jiang⁵, Zhengfei Yang⁶, Wanchun Tang⁷

Affiliations

¹ Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China; Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
² Department of Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
³ Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
⁵ Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
⁷ Weil Institute of Emergency and Critical Care Research, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].

PMID: 30870654
DOI: 10.1016/j.molimm.2019.03.002

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. There are multiple cytokines involved in the process of sepsis. As an important upstream cytokine in inflammation, Interleukin-3 (IL-3) plays a crucial role during sepsis, however, its exact role is unclear. The purpose of this study is to discuss the role of IL-3 and its receptor in cecal ligation and puncture (CLP)-induced sepsis in a rat model. The Cluster of Differentiation 123 (CD123, IL-3 receptor alpha chain, IL-3Rac) antibody (anti-CD123) was used to directly target IL-3's receptor and alleviate the effect of IL-3 in the CLP + anti-CD123 group during the early stage of sepsis. CLP was performed in the CLP and CLP + anti-CD123 groups. The time points of observation included 12 h, 24 h, and 5d after the operation. The results showed that the rats in the CLP + anti-CD123 group had lower levels of lactate, serum tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6), and also exhibited a higher core temperature, mean arterial pressure (MAP), Oxygenation Index (PO₂/FiO₂), and end-tidal carbon dioxide (ETCO₂) and serum Interleukin-10 (IL-10) levels after CLP than those in the CLP group. Additionally, administration of anti-CD123 led to a stable down-regulation of tyrosine phosphorylation of the IL-3 receptor, a decline in phosphorylation of the Janus kinase 2 (JAK2) protein, and the signal transduction and activation of transcription 5 (STAT5) proteins in lung tissues. Meanwhile, the study revealed that treatment of anti-CD123 can markedly attenuate histological damages in lung and kidney tissues, improve sublingual microcirculation, and prolong survival post sepsis. In conclusion, anti-CD123 reduces mortality and alleviates organ dysfunction by restraining the JAK2-STAT5 signaling pathway and reduces serum cytokines in the development of early sepsis in a rat model induced by CLP.

Keywords: Cecal ligation and puncture (CLP); IL-3; Sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / pharmacology
Cecum / pathology*
Disease Models, Animal
Inflammation Mediators / metabolism
Interleukin-3 / metabolism
Interleukin-3 Receptor alpha Subunit / metabolism
Kidney / drug effects
Kidney / pathology
Ligation
Lung / metabolism
Lung / pathology
Male
Microcirculation / drug effects
Punctures
Rats, Sprague-Dawley
Receptors, Interleukin-3 / antagonists & inhibitors*
Receptors, Interleukin-3 / metabolism
Sepsis / pathology*
Sepsis / prevention & control*
Signal Transduction / drug effects

Substances

Antibodies
Inflammation Mediators
Interleukin-3
Interleukin-3 Receptor alpha Subunit
Receptors, Interleukin-3