Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE

Abstract

Background The objective of the study was to explore the disease pathways activated in the inflammatory foci of skin lesions in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). Methods Skin biopsies acquired from active CLE and DM lesions, patient (PC), and also healthy controls (HC) were investigated. Biopsy sections were examined by a pathologist, inflammatory foci were laser micro-dissected and captured, and proteins within captured tissue were detected in an unbiased manner by mass spectrometry. Protein pathway analysis was performed by the string-db.org platform. Findings of interest were confirmed by immunohistochemistry (IHC). Results Proteome investigation identified abundant expression of interferon-regulated proteins (IRP) as a common feature of CLE and DM. Interleukin (IL)-16 was the only abundant cytokine differentially expressed in CLE compared to DM. Caspase-3, an enzyme that cleaves IL-16 into its active form, was detected in low levels. Significantly higher proportion of IL-16- and caspase-3-positive cells was identified in CLE lesions in comparison with DM, PC, and HC. Proteomic results indicate more abundant complement deposition in CLE skin lesions. Conclusions Using unbiased mass spectrometry investigation of CLE and DM inflammatory infiltrates, we confirmed that high IRP expression is a common feature of both CLE and DM, while IL-16 is the only differentially expressed cytokine in CLE. IHC confirmed high expression of IL-16 and caspase-3 in CLE. Our novel molecular findings indicate that IL-16 detection could be useful in differential diagnostics between the two conditions that can display similar histopathological appearance. IL-16 could be of interest as a future therapeutic target for CLE.

Cytokines as Biomarkers in Systemic Lupus Erythematosus: Value for Diagnosis and Drug Therapy

“…Among 30 tested cytokines, IL-16 was identified among the top five and increased concentrations in the circulation were found in patients with active nephritis. Also, in another unbiased analysis of cutaneous proteome of CLE lesions, IL-16 was identified as the only cytokine differentially upregulated in CLE in comparison to dermatomyositis (DM) [ 75 ]. These findings encourage further studies on the IL-16 role in SLE.…”

Proteomics Analysis of Plasma-Derived Exosomes Unveils the Aberrant Complement and Coagulation Cascades in Dermatomyositis/Polymyositis

“…ROC curve analysis also suggested that complement-associated proteins presented diagnostic performance with higher sensitivity and specificity. In addition, several studies have shown that the interaction of the complement system and interferon pathway perpetuates vascular injury. − Also, both complement-dependent microangiopathy and activation of the type I IFN pathway have been shown to play major roles in DM. , A model of the interferon-complement loop was proposed in transplant-associated thrombotic microangiopathy that contributes to perpetuating vascular endothelial damage and thrombotic microangiopathy. In this model, interferons promote the expression of C1q, resulting in the activation of the classical complement pathway and the formation of MAC and endothelial damage.…”

“… 35 − 37 Also, both complement-dependent microangiopathy and activation of the type I IFN pathway have been shown to play major roles in DM. 38 , 39 A model of the interferon-complement loop was proposed in transplant-associated thrombotic microangiopathy that contributes to perpetuating vascular endothelial damage and thrombotic microangiopathy. In this model, interferons promote the expression of C1q, resulting in the activation of the classical complement pathway and the formation of MAC and endothelial damage.…”

Interleukin (IL) 16: a candidate urinary biomarker for proliferative lupus nephritis

“…We have earlier reported increased levels of circulating IL-16 in patients with SLE and noted high levels in patients with LN 8. IL-16 was also identified as the most significantly enriched cytokine in both LE skin lesion and LN urine proteomes 9 10. IL-16 is a cytoplasmic protein cleaved by caspase-3 on various triggers.…”

“… 8 IL-16 was also identified as the most significantly enriched cytokine in both LE skin lesion and LN urine proteomes. 9 10 IL-16 is a cytoplasmic protein cleaved by caspase-3 on various triggers. After cleavage, a mature C-terminal IL-16 is secreted and involved in chemoattraction, migration and activation of CD4 T cells and may also mediate effects by binding to C-C chemokine receptor type 5 (CCR5) and CD9.…”