10.3389/fimmu.2019.01546.s001
Teja Celhar
Teja
Celhar
Hao Kim Lu
Hao Kim
Lu
Lia Benso
Lia
Benso
Larissa Rakhilina
Larissa
Rakhilina
Hui Yin Lee
Hui Yin
Lee
Shubhita Tripathi
Shubhita
Tripathi
Olga Zharkova
Olga
Zharkova
Wei Yee Ong
Wei Yee
Ong
Hiroko Yasuga
Hiroko
Yasuga
Bijin Au
Bijin
Au
Damien Marlier
Damien
Marlier
Lina Hsiu Kim Lim
Lina Hsiu Kim
Lim
Thomas Paulraj Thamboo
Thomas Paulraj
Thamboo
John S. Mudgett
John S.
Mudgett
Matthew F. Mackey
Matthew F.
Mackey
Dennis M. Zaller
Dennis M.
Zaller
John E. Connolly
John E.
Connolly
Anna-Marie Fairhurst
Anna-Marie
Fairhurst
Data_Sheet_1_TLR7 Protein Expression in Mild and Severe Lupus-Prone Models Is Regulated in a Leukocyte, Genetic, and IRAK4 Dependent Manner.pdf
Frontiers
2019
TLR7
IRAK4
anti-nuclear antibody
dendritic cells
SLE
lupus
2019-07-10 13:37:10
Dataset
https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_TLR7_Protein_Expression_in_Mild_and_Severe_Lupus-Prone_Models_Is_Regulated_in_a_Leukocyte_Genetic_and_IRAK4_Dependent_Manner_pdf/8851730
<p>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.</p>