Please use this identifier to cite or link to this item: https://doi.org/10.3389/fimmu.2019.01546
Title: TLR7 Protein Expression in Mild and Severe Lupus-Prone Models Is Regulated in a Leukocyte, Genetic, and IRAK4 Dependent Manner
Authors: Celhar, Teja
Lu, Hao Kim
Benso, Lia
Rakhilina, Larissa
Lee, Hui Yin
Tripathi, Shubhita
Zharkova, Olga 
Ong, Wei Yee
Yasuga, Hiroko
Au, Bijin
Marlier, Damien
Lim, Lina Hsiu Kim 
Thamboo, Thomas Paulraj 
Mudgett, John S
Mackey, Matthew F
Zaller, Dennis M
Connolly, John E 
Fairhurst, Anna-Marie 
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
TLR7
IRAK4
anti-nuclear antibody
dendritic cells
SLE
lupus
TOLL-LIKE RECEPTORS
CELL-INTRINSIC TLR7
AUTOANTIBODY PRODUCTION
KINASE-ACTIVITY
RISK HAPLOTYPE
ERYTHEMATOSUS
ASSOCIATION
DISEASE
DEFICIENCY
CLASSIFICATION
Issue Date: 10-Jul-2019
Publisher: FRONTIERS MEDIA SA
Citation: Celhar, Teja, Lu, Hao Kim, Benso, Lia, Rakhilina, Larissa, Lee, Hui Yin, Tripathi, Shubhita, Zharkova, Olga, Ong, Wei Yee, Yasuga, Hiroko, Au, Bijin, Marlier, Damien, Lim, Lina Hsiu Kim, Thamboo, Thomas Paulraj, Mudgett, John S, Mackey, Matthew F, Zaller, Dennis M, Connolly, John E, Fairhurst, Anna-Marie (2019-07-10). TLR7 Protein Expression in Mild and Severe Lupus-Prone Models Is Regulated in a Leukocyte, Genetic, and IRAK4 Dependent Manner. FRONTIERS IN IMMUNOLOGY 10 (JULY). ScholarBank@NUS Repository. https://doi.org/10.3389/fimmu.2019.01546
Abstract: © 2019 Celhar, Lu, Benso, Rakhilina, Lee, Tripathi, Zharkova, Ong, Yasuga, Au, Marlier, Lim, Thamboo, Mudgett, Mackey, Zaller, Connolly and Fairhurst. The global increase in autoimmunity, together with the emerging autoimmune-related side effects of cancer immunotherapy, have furthered a need for understanding of immune tolerance and activation. Systemic lupus erythematosus (SLE) is the archetypical autoimmune disease, affecting multiple organs, and tissues. Studying SLE creates knowledge relevant not just for autoimmunity, but the immune system in general. Murine models and patient studies have provided increasing evidence for the innate immune toll like receptor-7 (TLR7) in disease initiation and progression. Here, we demonstrated that the kinase activity of the TLR7-downstream signaling molecule, interleukin-1 receptor associated kinase 4 (IRAK4), is essential for mild and severe autoimmune traits of the Sle1 and Sle1-TLR7 transgenic (Sle1Tg7) murine models, respectively. Elimination of IRAK4 signaling prevented all pathological traits associated with murine lupus, including splenomegaly with leukocyte expansion, detectable circulating antinuclear antibodies and glomerulonephritis, in both Sle1 and Sle1Tg7 mice. The expansion of germinal center B cells and increased effector memory T cell phenotypes that are typical of lupus-prone strains, were also prevented with IRAK4 kinase elimination. Analysis of renal leukocyte infiltrates confirmed our earlier findings of an expanded conventional dendritic cell (cDC) within the kidneys of nephritic mice, and this was prevented with IRAK4 kinase elimination. Analysis of TLR7 at the protein level revealed that the expression in immune cells is dependent on the TLR7-transgene itself and/or autoimmune disease factors in a cell-specific manner. Increased TLR7 protein expression in renal macrophages and cDCs correlated with disease parameters such as blood urea nitrogen (BUN) levels and the frequency of leukocytes infiltrating the kidney. These findings suggest that controlling the level of TLR7 or downstream signaling within myeloid populations may prevent chronic inflammation and severe nephritis.
Source Title: FRONTIERS IN IMMUNOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/176660
ISSN: 16643224
DOI: 10.3389/fimmu.2019.01546
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