Borrelia burgdorferi Induces TLR2-Mediated Migration of Activated Dendritic Cells in an Ex Vivo Human Skin Model.

Lauren M K Mason,Cornelis Van ‘T Veer,Alex Wagemakers,Wouter J Van Der Pot,Teunis B H Geijtenbeek,Joppe W R Hovius,Kalam Ahmed,Anneke Oei,Tom Van Der Poll,Brian Stevenson

doi:10.1371/journal.pone.0164040

Lauren M K Mason, Cornelis Van ‘T Veer + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0164040

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Journal: PloS one	Publication Date: Oct 3, 2016
Citations: 19	License type: CC BY 4.0

Affiliation: Academic Medical Center, Spaarne Gasthuis

Abstract

Borrelia burgdorferi is transmitted into the skin of the host where it encounters and interacts with two dendritic cell (DC) subsets; Langerhans cells (LCs) and dermal DCs (DDCs). These cells recognize pathogens via pattern recognition receptors, mature and migrate out of the skin into draining lymph nodes, where they orchestrate adaptive immune responses. In order to investigate the response of skin DCs during the early immunopathogenesis of Lyme borreliosis, we injected B. burgdorferi intradermally into full-thickness human skin and studied the migration of DCs out of the skin, the activation profile and phenotype of migrated cells. We found a significant increase in the migration of LCs and DDCs in response to B. burgdorferi. Notably, migration was prevented by blocking TLR2. DCs migrated from skin inoculated with higher numbers of spirochetes expressed significantly higher levels of CD83 and produced pro-inflammatory cytokines. No difference was observed in the expression of HLA-DR, CD86, CD38, or CCR7. To conclude, we have established an ex vivo human skin model to study DC-B. burgdorferi interactions. Using this model, we have demonstrated that B. burgdorferi-induced DC migration is mediated by TLR2. Our findings underscore the utility of this model as a valuable tool to study immunity to spirochetal infections.

Highlights

Lyme borreliosis is caused by Borrelia burgdorferi sensu lato, a bacteria which is transmitted into the skin through infected Ixodes tick bites [1]
Langerhans cells (LCs) and dendritic cells (DDCs) were differentiated on the basis of CD1a and Langerin staining [14, 15] (Fig 2a); CD1ahi/Langerin+ LCs contributed to merely 2–6% of the total dendritic cell (DC)
We have established an ex vivo human skin model to study the response of DCs to entry of Borrelia burgdorferi into the skin

Summary

Introduction

Lyme borreliosis is caused by Borrelia burgdorferi sensu lato, a bacteria which is transmitted into the skin through infected Ixodes tick bites [1]. Upon entering the skin the bacteria is recognized by cells of the immune system, such as dendritic cells (DCs). Two subsets of DC reside in the skin; epidermal Langerhans cells (LCs) and dermal dendritic cells (DDCs). These are among the first cells that B. burgdorferi encounter upon transmission [3]. TLR2 has been acknowledged as one of the principal PRRs involved in recognition of borrelial lipoproteins such as outer surface protein C (OspC) [4, 5]. DCs have been shown in vitro to phagocytose B. burgdorferi, produce cytokines and gain a more mature phenotype, characterized by enhanced expression of cell-surface markers such as CD83 and CD86 and the antigen presenting molecule major histocompatibility complex (MHC)-II [6, 7]. LCs containing B. burgdorferi are found abundantly in erythema migrans lesions [8], it is unclear whether they play a role in immunity against B. burgdorferi, as LCs have a low expression of TLR2 and their contribution to anti-bacterial immunity is uncertain [9, 10]

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