Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways

Abstract

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN) response signatures in tubular cells and in keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

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

“…In line with recent reports that the presence of an IFN signature in keratinocytes associates with lupus nephritis, as well as with an IFN-I response in the kidney tissue (Der et al, 2017;Der et al, 2019), we observed an increase in ISG and Sca-1 expression levels in kidneys 24hr after skin exposure to UVB (Fig. 3F-G).…”

“…To test the relevance of our acute model of UV light-triggered IFN-I response in human skin, we exposed healthy volunteers (n=5, female) to a single dose of UV light (2 MED for UVB) and performed RNA sequencing on skin biopsies from unexposed skin and skin collected 6hr and 24hr after UV exposure. Using a published set of IFN-I response genes (Der et al, 2019), we demonstrated that a single UV exposure triggered an IFN-I signature in healthy skin as early as 6hr ( Fig. 1C-D).…”

“…More recently, the IFN signature in PBMC was reported in patients with cutaneous lupus (Braunstein et al, 2012) and the IFN signature in SLE skin has been linked to a similar signature in lupus nephritis (Der et al, 2017;Der et al, 2019). A key question in SLE is whether the IFN signature detected in PBMC is generated in blood or in tissues and, if in tissues, which tissues are responsible?…”

“…IFN score analysis: IFN-I scores at 6 (n=3) and 24hr (n=5) after UV were derived using the established IFN-I response gene dataset (188 of 212 genes were detected (Der et al, 2019).…”

“…(C-E) IFN-I response was evaluated in healthy human volunteers 6 and 24hr after UV exposure (2 MED UVB) and the ISG most differentially expressed shown in the heatmap (C). IFN scores were derived based on (D) 188 published IFN-I response genes(Der et al, 2019) or (E) 7 ISGs used in mouse studies (B). Statistical significance was determined by (A-B) Student's t-test (n=4-5, *p<0.05, **p<0.01) or (D-E) one-way ANOVA (n=3-5, **p<0.01, ****p<0.0001).…”