Network analysis of inflammatory responses to sepsis by neutrophils and peripheral blood mononuclear cells.

Rasoul Godini,Esmaeil Ebrahimie,Hossein Fallahi,Amarjit Mishra

doi:10.1371/journal.pone.0201674

Abstract

Sepsis is a life-threatening syndrome causing thousands of deaths yearly worldwide. Sepsis is a result of infection and could lead to systemic inflammatory responses and organ failures. Additionally, blood cells, as the main cells in the immune systems, could be also affected by sepsis. Here, we have used different network analysis approaches, including Weighted Gene Co-expression Network Analysis (WGCNA), Protein-Protein Interaction (PPI), and gene regulatory network, to dissect system-level response to sepsis by the main white blood cells. Gene expression profiles of Neutrophils (NTs), Dendritic Cells (DCs), and Peripheral Blood Mononuclear Cells (PBMCs) that were exposed to septic plasma were obtained and analyzed using bioinformatics approaches. Individual gene expression matrices and the list of differentially expressed genes (DEGs) were prepared and used to construct several networks. Consequently, key regulatory modules and hub genes were detected through network analysis and annotated through ontology analysis extracted from DAVID database. Our results showed that septic plasma affected the regulatory networks in NTs, PBMCs more than the network in DCs. Gene ontology of DEGs revealed that signal transduction and immune cells responses are the most important biological processes affected by sepsis. On the other hand, network analysis detected modules and hub genes in each cell types. It was found that pathways involved in immune cells, signal transduction, and apoptotic processes are among the most affected pathways in the responses to sepsis. Altogether, we have found several hub genes including ADORA3, CD83 CDKN1A, FFAR2, GNAQ, IL1B, LTB, MAPK14, SAMD9L, SOCS1, and STAT1, which might specifically respond to sepsis infection. In conclusion, our results uncovered the system-level responses of the main white blood cells to sepsis and identified several hub genes with potential applications for therapeutic and diagnostic purposes.

Highlights

Sepsis, a life-threatening condition, occurs when the immune reaction against an infection diverted toward the healthy cells in the body
Treatment of NT cells with septic plasma resulted in significant changes in the expression of 633 genes, much fewer genes, 387 and 270 differentially expressed genes (DEGs) were affected by sepsis in Peripheral Blood Mononuclear Cells (PBMCs) and Dendritic Cells (DCs), respectively (Fig 1a)
We found only 23 common DEGs among all type of cells, where 8 genes were down-regulated and 15 genes shown up-regulation (Fig 1c). Gene ontology of these 23 common DEGs showed that apoptotic process (TRAF1, TNFRSF9, ADORA2A, ZBTB16), negative regulation of transcription (SAP30, TSC22D3, ETS2, ZBTB16), and inflammatory response (TNFRSF9, CCL3, ADORA2A) are the main biological processes affected by sepsis treatment

Summary

Introduction

A life-threatening condition, occurs when the immune reaction against an infection diverted toward the healthy cells in the body. Serious conditions including organ dysfunction and hypotension refractory have been observed in “severe sepsis” and “septic shock”, respectively [1]. A link between “cytokine storm” and sepsis has been established, which is defined as the abnormal increase in the levels of different cytokines, including tumor necrosis factor (TNF) and interleukin-1 (IL-1) [4]. Perturbations in the cardiovascular system, acute kidney injuries, encephalopathy, and immobility are among organ-level responses to sepsis. Sepsis has associated with the alterations in many cellular processes including inflammatory signaling, metabolic pathways, and resolution pathways [5]

Methods

Results

Conclusion