Immunomodulation of endothelial cells induced by macrolide therapy in a model of septic stimulation.

Stéphanie Pons,Juliette Ferry,Lara Zafrani,Nuala Mooney,Eden Arrii,Manel Nouacer,Julien Lion,Maud Loiselle,Shannon Cohen,Marine Arnaud

doi:10.1002/iid3.518

Abstract

ObjectivesSepsis is defined as the host's inflammatory response to a life‐threatening infection. The endothelium is implicated in immunoregulation during sepsis. Macrolides have been proposed to display immunomodulatory properties. The goal of this study was to analyze whether macrolides can exert immunomodulation of endothelial cells (ECs) in an experimental model of sepsis.MethodsHuman ECs were stimulated by proinflammatory cytokines and lipopolysaccharide before exposure to macrolides. ECs phenotypes were analyzed by flow cytometry. Cocultures of ECs and peripheral blood mononuclear cells (PBMCs) were performed to study the ECs ability to alter T‐cell viability and differentiation in the presence of macrolides. Soluble factor production was assessed.ResultsECs act as non‐professional antigen presenting cells and expressed human leukocyte antigen (HLA) antigens, the adhesion molecules CD54, CD106, and the coinhibitory molecule CD274 after septic stimulation. Incubation with macrolides induced a significant decrease of HLA class I and HLA class II HLA‐DR on septic‐stimulated ECs, but did not alter either CD54, CD106, nor CD274 expression. Interleukin‐6 (IL‐6) and IL‐8 production by stimulated ECs were unaltered by incubation with macrolides, whereas Clarithromycin exposure significantly decreased IL‐6 gene expression. In cocultures of septic ECs with PBMCs, neither the proportion of CD4 + , CD8 + T nor their viability was altered by macrolides. T‐helper lymphocyte subsets Th1, Th17, and Treg polarization by stimulated ECs were unaltered by macrolides.ConclusionThis study reports phenotypic and gene expression changes in septic‐stimulated ECs exposed to macrolides, without resulting in altered immunogenicity of ECs in co‐cultures with PBMCs. In vivo studies may help to further understand the impact of macrolide therapy on ECs immune homeostasis during sepsis.

Highlights

Sepsis is defined as the host's inflammatory response to a life‐threatening infection.[1]
To further investigate the effects of macrolides on molecules upregulated during sepsis, we studied surface expression of CD54, CD106 involved in leukocytes adhesion and CD274 (PDL‐1) a T‐lymphocyte inhibitor costimulatory molecule
Because of their potential immunoregulating properties associated with their activity against atypical intracellular pathogens, macrolides are frequently used in critically ill patients with severe community acquired pneumonia (CAP)

Summary

Introduction

Sepsis is defined as the host's inflammatory response to a life‐threatening infection.[1] Sepsis induces immune dysregulation with the initiation of a strong inflammatory response This occurs secondary to the binding of pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs) to pattern recognition receptors such as Toll‐like receptors (TLRs) and Nod‐like receptors (NLRs) and contributes to organ failure.[2] Immune suppression and exhaustion occur in parallel with hyper‐inflammation and predispose patients to secondary infections, reactivation of latent viruses[3] and late deaths.[4] Septic shock is the most important cause of mortality in intensive care unit (ICU), despite many improvements in care that have been made in the past 10 years. They analyzed the effects of low‐dose macrolides administered for nonantibiotic purposes on 30‐day mortality.

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