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Intermedin1–53 Protects Cardiac Fibroblasts by Inhibiting NLRP3 Inflammasome Activation During Sepsis

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Abstract

Sepsis is a disease that occurs as a result of systemic inflammatory response syndrome (SIRS) in response to an infection, contributing to multiple organ dysfunction and a high mortality rate. Interleukin-lβ (IL-1β) is a cytokine that plays critical roles in inflammation and cardiac dysfunction during severe sepsis. Intermedin1–53 (IMD1–53) has been recently discovered to possess potential endogenous anti-inflammatory and strong cardiovascular protective effects. To investigate whether IMD1–53 can inhibit the NLRP3/caspase-1/IL-1β pathway to alleviate cardiac injury and rescue heart function, sepsis was induced in vivo by caecal ligation and puncture (CLP) surgery, and lipopolysaccharides were used as septic stressors for cardiac fibroblasts (CFs) in vitro. The expressions of IMD1–53 receptors in sepsis rat heart were increased. After IMD1–53 treatment, inflammation caused by sepsis in vivo was greatly reduced, as shown by the downregulation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), nucleotide-binding domain and leucine-rich repeat containing family, pyrin containing 3 (NLRP3), pro-IL-1β, caspase 1, and nuclear translocation of nuclear factor-κB (NF-kB) protein levels. In addition, cardiac function was significantly improved and mean arterial blood pressure (MABP) increased by 34.8% (P < 0.05) which almost back to normal. Surprisingly, IMD1–53 inhibited cell apoptosis, as caspase 3 activity and Bax expression was significantly reduced in the heart upon IMD1–53 treatment. IMD1–53 abolished the upregulation of ASC, NLRP3, and caspase 1 protein levels in CFs induced by lipopolysaccharide (LPS). IMD1–53 increased cell survival rates and inhibited IL-1β production in the cell culture medium. IMD1–53 can protect against inflammation and heart injury during sepsis via attenuating the NLRP3/caspase-1/IL-1β pathway.

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Acknowledgments

This study is supported by the Research Foundation of the Aerospace Central Hospital (NO. YN201316 to Bin Wang) and the National Natural Sciences Foundation of China (NO. 81670434 to Yongfen Qi).

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  1. Yongfen Qi and Bin Wang contributed equally to this work.

Authors and Affiliations

  1. The Peking University Aerospace School of Clinical Medicine, Peking University Health Science Center, Beijing, 100191, China

    Di Wu & Bin Wang

  2. The Peking University People’s Hospital, Beijing, 100191, China

    Lin Shi

  3. Texas Heart Institute, Houston, TX, 77030, USA

    Pengyang Li

  4. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China

    Xianqiang Ni, Jinsheng Zhang, Qing Zhu & Yongfen Qi

  5. The First Affiliated Hospital of Shantou University Medical College, Guangdong, 515041, China

    Bin Wang

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  1. Di Wu
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Wu, D., Shi, L., Li, P. et al. Intermedin1–53 Protects Cardiac Fibroblasts by Inhibiting NLRP3 Inflammasome Activation During Sepsis. Inflammation 41, 505–514 (2018). https://doi.org/10.1007/s10753-017-0706-2

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