TY - JOUR
T1 - Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility
AU - De Groof, Aurélie
AU - Ducreux, Julie
AU - Vidal-Bralo, Laura
AU - Tyteca, Donatienne
AU - Galant, Christine
AU - Marot, Liliane
AU - Coulie, Pierre G.
AU - van den Eynde, Benoît J.
AU - Rodriguez-Martinez, Lorena
AU - Santos, Maria Jose
AU - Suarez, Ana
AU - Carreira, Patricia
AU - Marchini, Maurizio
AU - Gonzàlez, Antonio
AU - Houssiau, Frédéric A.
AU - Lauwerys, Bernard R.
N1 - Funding Information:
this work was supported by grants from the WELBIO, Fonds National de la Recherche Scientifique and Fonds Sp?ciaux pour la Recherche (Communaut? fran?aise de Belgique), and by Instituto de Salud Carlos III (grants PI11/01048 and RD12/0009/0008 that are partially financed by the European Regional Development Fund of the European Union). A. De Groof is funded by WELBIO. J. Ducreux is partly funded by a UCB ?Chaire en rhumatismes inflammatoires et syst?miques? grant. B. Lauwerys is partly funded by the Fonds National de la Recherche Scientifique.
Publisher Copyright:
© Copyright CliniCal and ExpErimEntal rhEumatology 2020.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Objective 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. Conclusion 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.
AB - Objective 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. Conclusion 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.
KW - Antigen-presenting cell
KW - Apoptosis
KW - Ro/SSA autoantigen
KW - Systemic lupus erythematosus
KW - TLR3
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M3 - Article
C2 - 31969218
AN - SCOPUS:85092593563
VL - 38
SP - 881
EP - 890
JO - Clinical and Experimental Rheumatology
JF - Clinical and Experimental Rheumatology
SN - 0392-856X
IS - 5
ER -