Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

Abstract

Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

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

“…1A). Similar to a previous report using ex vivo samples (Sarkar et al, 2018), we detected a modest (~2-fold) and transient (6 hr) IFN-κ expression in the skin (not shown). Early induction in cutaneous expression of all the tested ISG was strikingly higher in female than in male mice, and the greater fold-induction of some ISG in female skin persisted at 24hr (Ifit3 and Ifif44) and 48hr (Ifit3 and Irf7) after UVB exposure ( Fig.…”

“…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).…”

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity

“…To examine the effects of VGLL3 that were driving this lupus-like cutaneous phenotype, we evaluated WT mice and robustly expressing transgenic mice by qRT-PCR for transcript levels of a panel of proinflammatory and lupus-related factors. Many of these transcripts showed significant elevation in transgenic mice (Figure 2A and Supplemental Figure 2A), including Tnfsf13b (encoding BAFF); IFN-κ (Ifnk), the predominant type I IFN in cutaneous lupus (5); and Cxcl13, a biomarker of early-onset SLE, heightened disease activity, and renal involvement (6). IF studies of key VGLL3-regulated factors ( Figure 2B) corroborated our qRT-PCR findings.…”

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…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 .…”