Abstract
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.
Highlights
The immune system provides a crucial barrier against invasive pathogenic challenges
Analyses of kidney function showed expected increases in blood urea nitrogen (BUN) levels and urine albumin concentration in Sle1Tg7 mice compared to Sle1 controls, which were prevented in interleukin-1 receptor associated kinase 4 (IRAK4) KD/KD mice (Figures 1B,C)
Histopathology demonstrated that Sle1Tg7 kidneys had global endocapillary proliferation with cellular crescents in the glomeruli, while kidneys from Sle1, Sle1IRAK4KD/KD, and Sle1Tg7IRAK4KD/KD mice showed only mild segmental mesangial proliferation (Figure 1D)
Summary
The immune system provides a crucial barrier against invasive pathogenic challenges. Defects can lead to opportunistic infections, cancer or the development of autoimmunity. Systemic lupus erythematosus (SLE) is the archetypical autoimmune disorder, whereby the immune system attacks itself in a systemic manner It is complex and is driven by both genetic and environmental factors with no effective prevention or cure [1, 2]. SLE is characterized by the development of anti-nuclear antibodies (ANAs), dsDNA- and RNA-reactive autoantibodies These bind to self-antigens, resulting in the formation of immune complexes (ICs) which deposit in tissues, initiating, and promoting inflammation, tissue destruction, and often culminating in organ failure [3]. TLR7 recognizes single-stranded RNA (ssRNA) and is central to host defense against invading viruses [5, 6]. It plays a fundamental role in the development and progression of autoimmunity. TLR7 mRNA expression is higher in PBMCs from SLE patients, with levels correlating with the expression of IFNα [9]
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