P17 A signature of IL-36 activation in systemic lupus erythematosus skin

Abstract Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with heterogeneous presentation. Joint and kidney disease represent the largest cause of morbidity, and visually distinctive skin complications are often present. While it has long been established that organ damage is caused by autoantibodies forming large immune complexes in the affected tissues, a detailed understanding of disease processes is still lacking. Here, we propose that interleukin (IL)-36 cytokines, which drive cutaneous and systemic symptoms in psoriasis, are also implicated in the pathogenesis of SLE. Given that the IL-36 receptor is prominently expressed in keratinocytes, we investigated this hypothesis in skin. We first carried out a systematic review of SLE single-cell RNA sequencing studies, identifying two data sets (∼50 000 cells in total) generated from patient skin biopsies. We processed both data sets with the same standardized pipeline, using the Seurat package. This identified 10 distinct cell clusters, replicating the cell types described in the original studies and identifying the main cell populations observed in human skin. Subsequent gene expression analysis confirmed that, in both data sets, the expression of IL36G and IL1RL2 (the genes encoding IL-36γ and its receptor) was highest in keratinocytes. Interestingly, subclustering showed that this signal was driven by the expression of IL36G in supraspinous keratinocytes and of IL1RL2 in proliferating keratinocytes. In the first data set, the expression of IL36G and IL1RL2 was readily detectable in lesional keratinocytes but virtually nonexistent in their nonlesional counterparts. A comparison of lesional and nonlesional keratinocytes also identified 297 differentially expressed genes (DEGs; log2 fold change > 1.2, false discovery rate < 0.05) in the first study and 234 in the second. To further explore these findings, we compared the above DEG with a set of 182 genes (previously defined by our group) that are upregulated in IL-36-stimulated keratinocytes. This demonstrated a significant over-representation of the IL-36 signature genes among the DEGs observed in lesional SLE keratinocytes (P < 0.005 in both data sets). These observations indicate that IL-36 is likely to contribute to skin inflammation in SLE, warranting further studies of this cytokine in organs affected by the disease.