Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility.

De Groof, Aurélie;Ducreux, Julie;Vidal-Bralo, Laura;Tyteca, Donatienne;Lauwerys, Bernard;et.al.
(2020) Clinical and Experimental Rheumatology — Vol. 38, n° 5, p. 881-890 (2020)

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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.
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De Groof, A., Ducreux, J., Vidal-Bralo, L., Tyteca, D., Galant, C., Marot, L., Coulie, P., Van den Eynde, B., Rodriguez-Martinez, L., Santos, M. J., Suarez, A., Carreira, P., Marchini, M., Gonzàlez, A., Houssiau, F., & Lauwerys, B. (2020). Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility. Clinical and Experimental Rheumatology, 38(5), 881-890. https://hdl.handle.net/2078.5/169618 (Original work published 2020)