Full Papers
Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility
A. De Groof1, J. Ducreux2, L. Vidal-Bralo3, D. Tyteca4, C. Galant5, L. Marot6, P.G. Coulie7, B.J. Van Den Eynde8, L. Rodriguez-Martinez9, M.J. Santos10, A. Suarez11, P. Carreira12, M. Marchini13, A. Gonzàlez14, F.A. Houssiau15, B.R. Lauwerys16
- Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
- Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
- Instituto de Investigacion Sanitaria and Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
- Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, and Pôle de Morphologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
- Department of Dermatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
- de Duve Institute, and Ludwig Institute for Cancer Research, Université Catholique de Louvain, Brussels, Belgium.
- Instituto de Investigacion Sanitaria and Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
- Hospital Garcia de Orta, Almada, Portugal.
- Department of Functional Biology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Spain.
- Department of Rheumatology Hospital 12 de Octubre, Madrid, Spain.
- Center for Systemic Autoimmune Diseases, Fondazione IRCCS & Granda Ospedale Maggiore Policlinico and University of Milan, Italy.
- Instituto de Investigacion Sanitaria and Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
- Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, and Department of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Univ. Catholique de Louvain, and Dept.of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. bernard.lauwerys@uclouvain.be
CER12596
2020 Vol.38, N°5
PI 0881, PF 0890
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PMID: 31969218 [PubMed]
Received: 15/07/2019
Accepted : 30/09/2019
In Press: 20/01/2020
Published: 02/10/2020
Abstract
OBJECTIVES:
TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility.
METHODS:
Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNβ immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls.
RESULTS:
TLR3 and IFNβ are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls.
CONCLUSIONS:
TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.
