TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling

Wolf, Sonya; Theros, Jonathan; Reed, Tammi J.; Jian-hua, Liu; Grigorova, Irina; Martínez-Colón, Giovanny J.; Jacob, Chaim O.; Hodgin, Jeffrey B.; Kahlenberg, J. Michelle

doi:10.4049/jimmunol.1701588

Cited by 29 publications

(23 citation statements)

References 47 publications

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“…Other types of skin injury such as tape stripping and topical application of a TLR7 agonist have been reported to enhance kidney injury in certain lupus models, although disease enhancement was thought to be mediated by macrophages and dendritic cells rather than neutrophils 68,69 . Having demonstrated that tape stripping did not lead to neutrophil recruitment to the kidney, we propose that UV light exposure is different from other types of sterile skin inflammation and is more relevant to SLE.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.

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Section: Discussionmentioning

confidence: 99%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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“…This inducible model was adopted to study mechanisms of TLR7 action in systemic autoimmunity, and was successfully used to investigate TLR7/TLR9 imbalance in lupus vasculopathy as well as autoimmune-mediated myocarditis (12,13). TLR7 agonism has the additional benefit of rapid onset of action, and is also being used as an accelerant in spontaneous lupus murine models (14). Herein we utilized this inducible model in WT C57BL/6j (B6) mice to determine if topical TLR7 agonism triggered significant autoimmune-mediated nephritis, since data on this is lacking in the prior publications, and we additionally tested whether it accelerates disease expression in lupus-prone NZM2410 mice.…”

Section: Introductionmentioning

confidence: 99%

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

et al. 2020

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Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.

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“…A recent study also showed that polymorphisms in the promoter of TLR7 were associated with SLE (Skonieczna et al, 2018). Finally, while pDCs secrete increased levels of type I IFN in a TLR7-mediated manner in SLE patients (Murayama et al, 2017), lupus nephritis was recently shown to be independent of type I IFN yet remained dependent on TLR7 signaling (Wolf et al, 2018). …”

Section: Rna Nucleic Acid Sensing In Viral Immunology and Autoimmunitymentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling

Cited by 29 publications

References 47 publications

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

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