Progranulin (PGRN) is a growth factor and immune regulatory protein involved in the regulation of host-defense signaling pathways during infection and inflammation. It is critical in innate immunity against bacteria and targets TLR4 which recognizes LPS (1–3). Progranulin deficiency in animal models leads to increased vulnerability to LPS-induced septic shock and high mortality (1). Increased progranulin plasma levels have been described in in patients with sepsis (4).
Exciting research on progranulin as a novel biomarker was recently presented at the Sepsis Update 2019 conference which took place on September 11–13 in Weimar, Germany. QIAGEN’s Senior Principal Scientist for Bioinformatics, Dr. Jean-Noel Billaud, collaborated on this research with Dr. Gustav Schelling’s team from Klinikum der Universität München, who presented their progranulin research findings at the conference. The aim of their research was to study the performance characteristics of progranulin as a potential biomarker for sepsis, compared to established markers such as procalcitonin (PCT), and to delineate molecular networks involved in upregulating progranulin in sepsis.
To achieve this, the team used QIAGEN bioinformatics software OmicSoft ArrayStudio to obtain the differentiation profile after DESEq2 analysis, and performed biological interpretation using Ingenuity Pathway Analysis (IPA). NGS data from sepsis patient samples were used to identify the canonical gene network (targeted miRNA-mRNA network) involved in the early antimicrobial response of progranulin, followed by RT-qPCR confirmation.
NGS revealed significantly upregulated mRNA transcripts of GRN from human blood cell samples (the progranulin gene) (log2FC = 2.23, padj=3.46E-8) and SORT1 (sortilin, an important regulator of progranulin) (log2FC = 5.56, padj=1.38E-8), whereas comprehensive NGS did not detect any transcripts of CALC-1 (PCT) in blood cells. Filtering and pairing of NGS miRNA/mRNA data using IPA revealed a network (Figure 1) including TP53 and TLR4 as well as progranulin and sortilin, shown to be regulated by miR-16, miR-150 and others. The miRNAs and mRNAs from the network, including progranulin and sortilin, were confirmed by RT-qPCR.
Figure 1. Upregulation of progranulin (GRN gene transcript) in a molecular network activated during early antimicrobial response in septic shock. The network was constructed using high-throughput sequencing (NGS) followed by RT-qPCR confirmation. Red indicates upregulation of the respective molecules and green indicates downregulation.
This research performed using QIAGEN bioinformatics solutions indicates how progranulin is part of a key blood-cell derived network involved in early antimicrobial response in sepsis, and performs just as well as other more established biomarkers for the differentiation between systemic inflammatory response syndrome (SIRS) and sepsis. Based on this research progranulin represents a novel and sensitive biomarker for sepsis.
References.
1. Jian J, Konopka J and Liu C. (2013) Insights into the role of progranulin in immunity, infection, and inflammation. J Leukoc Biol 93: 199–208.
2. McIsaac SM, Stadnyk AW and Lin TJ. (2012) Toll-like receptors in the host defense against Pseudomonas aeruginosa respiratory infection and cystic fibrosis. J Leukoc Biol 92: 977–985.
3. Abella V, et al (2016). The novel adipokine progranulin counteracts IL-1 and TLR4-driven inflammatory response in human and murine chondrocytes via TNFR1. Sci Rep 6: 20356.
4. Yan W, et al. (2016) Progranulin Controls Sepsis via C/EBPalpha-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation. J Immunol 197: 3393–3405.