Selective Activation of Human Dendritic Cells by OM-85 through a NF-kB and MAPK Dependent Pathway

Carmen Parola,Valentina Salvi,Tiziana Musso,Paolo Somma,Marco Bardessono,Alberto Mantovani,Sara Scutera,Giuseppe Tabbia,Laura Salogni,Xenia Vaira,Silvano Sozzani,Daniela Bosisio,Christian Pasquali

doi:10.1371/journal.pone.0082867

Abstract

OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), a product made of the water soluble fractions of 21 inactivated bacterial strain patterns responsible for respiratory tract infections, is used for the prevention of recurrent upper respiratory tract infections and acute exacerbations in chronic obstructive pulmonary disease patients. OM-85 is able to potentiate both innate and adaptive immune responses. However, the molecular mechanisms responsible for OM-85 activation are still largely unknown. Purpose of this study was to investigate the impact of OM-85 stimulation on human dendritic cell functions. We show that OM-85 selectively induced NF-kB and MAPK activation in human DC with no detectable action on the interferon regulatory factor (IRF) pathway. As a consequence, chemokines (i.e. CXCL8, CXCL6, CCL3, CCL20, CCL22) and B-cell activating cytokines (i.e. IL-6, BAFF and IL-10) were strongly upregulated. OM-85 also synergized with the action of classical pro-inflammatory stimuli used at suboptimal concentrations. Peripheral blood mononuclear cells from patients with COPD, a pathological condition often associated with altered PRR expression pattern, fully retained the capability to respond to OM-85. These results provide new insights on the molecular mechanisms of OM-85 activation of the immune response and strengthen the rational for its use in clinical settings.

Highlights

In the last ten years, it has become increasingly clear that dendritic cell (DC) activation is one of the key steps leading to the induction and polarization of the immune and inflammatory response
We report that OM-85 induces the secretion of a defined set of cytokines by human DC through the NF-kB and MAPK pathways, which are activated downstream of the vast majority of pattern recognition receptors (PRR)
OM-85 did not activate the interferon regulatory factor (IRF) pathway in these cells and experimental conditions, suggesting that TLR4, endosomal Toll-like receptors (TLR) and RIG-1-like receptors (RLR) may not be involved in OM-85 recognition and signaling

Summary

Introduction

In the last ten years, it has become increasingly clear that dendritic cell (DC) activation is one of the key steps leading to the induction and polarization of the immune and inflammatory response. The innate immune system sense microbes by multiple classes of pattern recognition receptors (PRR), including Toll-like receptors (TLR), NOD-like receptors (NLR), RIG-1-like receptors (RLR) and C-type lectins. Pathogen recognition by PRR activates a transcriptional program leading to the synthesis of molecules required for a rapid, efficient and pathogen-tailored immune-response. PRR sensing extracellular microbes (such as TLR2, TLR5 and some C-type lectins) activate a NF-kB- and MAPK-dependent production of pro-inflammatory cytokines, while PRR recognizing intracellular pathogen-associated molecular patterns (PAMP) (e.g. TLR7-9 and RIG-1) lead to the activation of the interferon regulatory factor (IRF) family of transcription factors and to the production of type I Interferons. Pathogen recognition induces DC maturation to professional antigen presenting cells, characterized by the expression of co-stimulatory molecules and by a ‘‘switch’’ in the expression of chemotactic receptors that enables them to travel to secondary lymphoid organs, where they meet naıve T cells [4]

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Results

Conclusion