Background Many investigators have explored pathways upregulated in SLE and CLE. Few reports studied key downregulated pathways and mediators. Using unbiased proteomic technique, we have previously identified IL-16 as a key cytokine in cutaneous lupus erythematosus (CLE), and findings were verified lupus nephritis.^{1 2} In this analysis we analysed the downregulated pathways in the same proteomic database.

Objectives To systematically identify patterns of protein expression in dermal infiltrates of skin lesions of patients with CLE in comparison to control skin, and explore what pathways might be downregulated or non-functional.

Methods Skin biopsies from 6 CLE patients and 6 controls were investigated as described before.² Inflammatory infiltrates and control dermis were laser capture micro-dissected and run on nano-LC tandem mass spectrometry.

Data was analysed by String and Qiagen Ingenuity pathway analysis (IPA). P-values<0.05 were considered significant, adjustment for multiple testing was performed.

Results Comparing CLE vs controls we identified 300 proteins that were upregulated in CLE, while 387 were downregulated.

The IPA of the upregulated pathways was presented before,² and include interferon, EIF2, hyper-cytokinemia, mitochondrial dysfunction, RHOGDI signalling, Th1 and Th2, granzyme A pathways.

There were a high number of downregulated pathways, which included remodelling of epithelial adherent junctions, fatty acid a-oxidation, Sertoli-cell junction, GP6, apelin liver, wound healing, and a list of downregulated degradation pathways for tryptophan X, putrescine, dopamine, valine, histamine, noradrenaline and adrenaline, ethanol; followed by integrin and epithelial adherent junction signaling, oxidative phosphorylation, estrogen receptor and intrinsic phrothrombin activation. Overlapping among several pathways, components of respiratory chain (NADH dehydrogenase and multiple subcomponents), galectin 3 and 7, epidermal growth factor receptor (EGFR), interleukin-1 receptor antagonist protein (IL1RN) and integrin alpha 2 (ITGA2) were significantly downregulated, while for example ITGA beta 2 (ITGAB2) was strongly upregulated.²

Conclusions Comparative analysis of upregulated and downregulated pathways at the site of skin inflammation, have disclosed several key-components that are downregulated, possibly malfunctioning or dysbalanced in regulation of inflammation and tissue regeneration. This novel information may contribute to better understanding of disease molecular pathogenesis, and what pathways might be of interest for pharmaceutical targeting.

Acknowledgements Karolinska Institutet-Mayo Clinic collaboration fund, NCI Cancer Center Support Grant 5P30 CA15083–43C1, Signe och Reinhold Sunds fund and Margareta Nilsson foundation.

Disclosures Timothy Niewold: None declared; Alexander Meves: None declared; Julia Lehman: None declared; Karin Popovic-Silwerfeldt: None declared; Cristine Charlesworth: None declared; Benjamin Madden: None declared; Elisabet Svenungsson shareholder of: AstraZeneca, Pfizer, Speakers fee: Janssen, Grant/research support from: Merck; Vilija Oke Speakers fee: Novartis, Jansen, Astra Zeneca, UCB, Eli Lilly and Abbvie, Grant/research support from: Ono pharma.

References

1. Häyry A, Faustini F, Zickert A, et al. Interleukin (IL) 16: a candidate urinary biomarker for proliferative lupus nephritis. Lupus Sci Medicine 2022;9:e000744.

2. Niewold TB, Meves A, Lehman JS, et al. Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE. Arthritis Res Ther 2021;23:132.