Ultraviolet light induces increased T cell activation in lupus-prone mice via type I IFN-dependent inhibition of T regulatory cells

Wolf, Sonya; Estadt, Shannon N.; Theros, Jonathan; Moore, Tyson; Ellis, Jason S.; Liu, Jianhua; Reed, T. Edward; Jacob, Chaim O.; Guðjónsson, Jóhann E.; Kahlenberg, J. Michelle

doi:10.1016/j.jaut.2019.06.002

Cited by 42 publications

(35 citation statements)

References 36 publications

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“…In SLE, however, external stimuli such as bacterial infection, toxins, or ultraviolet (UV) light induce DNA damage and keratinocyte apoptosis. The resulting prolonged autoantigen exposure increases stimulation of host immune cell responses [ 126 ]. SLE also induces T-cell activation via suppression of Treg cells in a type I interferon (IFN)-dependent manner.…”

Section: Dysbiosis Of the Gut Microbiota And Related Diseasesmentioning

confidence: 99%

Gut Microbiota and Immune System Interactions

et al. 2020

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Dynamic interactions between gut microbiota and a host’s innate and adaptive immune systems play key roles in maintaining intestinal homeostasis and inhibiting inflammation. The gut microbiota metabolizes proteins and complex carbohydrates, synthesize vitamins, and produce an enormous number of metabolic products that can mediate cross-talk between gut epithelial and immune cells. As a defense mechanism, gut epithelial cells produce a mucosal barrier to segregate microbiota from host immune cells and reduce intestinal permeability. An impaired interaction between gut microbiota and the mucosal immune system can lead to an increased abundance of potentially pathogenic gram-negative bacteria and their associated metabolic changes, disrupting the epithelial barrier and increasing susceptibility to infections. Gut dysbiosis, or negative alterations in gut microbial composition, can also dysregulate immune responses, causing inflammation, oxidative stress, and insulin resistance. Over time, chronic dysbiosis and the translocation of bacteria and their metabolic products across the mucosal barrier may increase prevalence of type 2 diabetes, cardiovascular disease, inflammatory bowel disease, autoimmune disease, and a variety of cancers. In this paper, we highlight the pivotal role gut microbiota and their metabolites (short-chain fatty acids (SCFAs)) play in mucosal immunity.

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Section: Dysbiosis Of the Gut Microbiota And Related Diseasesmentioning

confidence: 99%

Gut Microbiota and Immune System Interactions

et al. 2020

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“…In vitro and ex vivo studies reported that UVB and UVC light-mediated cell damage induced IFN-I in keratinocytes and other cell types (Gehrke et al, 2013;Sarkar et al, 2018), possibly aided by the downregulation of ULK-1, a STING inhibitor (Kemp et al, 2015). We and others observed that repeated exposure to low doses of UVB light (100mJ/cm 2 per day for 5 days) caused a modest upregulation in ISG expression in the skin of normal mice (Sontheimer et al, 2017;Wolf et al, 2019). However, this subacute model generates cycles of inflammation and resolution, which complicates understanding as to whether IFN-I reflects immediate injury or a wound repair response.…”

Section: Resultsmentioning

confidence: 76%

“…Here, we observed that both local and systemic early production of IFN-I following skin exposure to UVB was almost entirely cGAS dependent. In normal situations, acute inflammation is resolved through many reparative mechanisms that involve T-regulatory cells, Langerhans cells, and anti-inflammatory cytokines such as IL-10 (Shipman et al, 2018;Wolf et al, 2019;Yamazaki et al, 2018). Why SLE patients fail to control the inflammatory response in the skin and elsewhere is a critical question that will benefit from understanding the pathogenetic pathways involved.…”

Section: Remarkably Uvb Exposure Induces a Systemic Ifn-i Response Amentioning

confidence: 99%

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent

Skopelja-Gardner

Tai

et al. 2019

Preprint

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AbstractMost systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.

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“…While we found that neutrophil-mediated kidney inflammation in response to UV light does not cause clinical disease in healthy mice, such a mechanism may contribute to LN flares in photosensitive lupus patients in multiple ways: Fc receptor engagement by immune complexes could enhance neutrophil recruitment resulting in ROS and protease release 105,106 ; the heightened capacity of lupus neutrophils and LDGs to produce NETs, which in SLE patients are not cleared efficiently 107,108 , could lead to release of tissue-damaging proteases 109,110 , propagation of the IFN-I response 85,86 , or direct damage to the kidney endothelium by creating vascular damage and leakage 14,111 . Moreover, the underlying differences in lupus skin, such as enhanced IFN-I signaling 7,112,113 and defects in protective Langerhans cell population 114 could inform the extent and nature of neutrophil-mediated systemic responses. The exact mechanism might in addition be influenced by the neutrophil/LDG phenotype, as heterogeneity within these populations has become more apparent in SLE 65 .…”

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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Ultraviolet light induces increased T cell activation in lupus-prone mice via type I IFN-dependent inhibition of T regulatory cells

Cited by 42 publications

References 36 publications

Gut Microbiota and Immune System Interactions

Gut Microbiota and Immune System Interactions

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

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