Session Type: Abstract Submissions (ACR)
Cutaneous lupus erythematosus (CLE) refers to variants of lupus erythematosus (LE) with exclusively or predominantly skin manifestations. CLE is associated with accumulation of autoantibodies and infiltration of inflammatory cells in the skin. The underlying trigger for autoimmunity in CLE has not been definitively identified. Apoptosis, which generates apoptotic bodies and apoptotic blebs, the latter also known as membrane microvesicles (MVs), have been proposed to play a central role in autoimmune diseases, particularly when normal mechanisms for clearance of apoptotic cells, bodies and MVs are impaired. We and others have shown that apoptotic MVs exert pro-inflammatory properties. The role of MVs in CLE has not been studied. In addition, tobacco smoking has emerged as a risk factor for CLE, particularly severe and refractory forms, but the underlying mechanisms are unclear. Our recent publications showed that exposure of human monocyte/macrophages to tobacco smoke extract (TSE) provokes apoptosis and the release of potent, biologically active MVs. LL-37 is a cathelicidin antimicrobial peptide with proinflammatory properties that has been described as a soluble molecule or released with neutrophil extracellular traps (NETs), and is involved in autoimmune diseases. In the current study, we hypothesized a role for MVs in CLE in the transport of LL-37, a cathelicidin antimicrobial peptide with proinflammatory properties.
Blood and skin biopsy samples were collected from CLE patients and healthy control subjects. Platelet-free plasma was isolated by sequential centrifugation. Freshly harvested skin samples were rinsed with PBS, and then minced into small pieces in DMEM for later analysis of MVs. Cultured human HL-60 neutrophils, THP-1 monocytes, and peripheral blood monocytic ce lls (PBMCs) were treated without or with tobacco smoke extract (TSE), and then the cells were examined by fluorescent microscopy, and the cells and supernatants were analyzed with flow cytometry.
We found that skin lesions of CLE patients contain MVs that carry LL-37. Flow cytometry analysis using cell-specific markers revealed that LL-37-positive MVs in CLE skin lesions are largely of neutrophil origin. In plasma, we found increased concentrations of circulating total- and LL-37-positive MVs in CLE patients, compared to healthy controls. Most importantly, we found that MVs isolated from the plasma of CLE patients can stimulate TNFα release from PBMCs. In addition, exposure of human HL-60 neutrophils, THP-1 monocytes, or PBMCs isolated from healthy volunteers to TSE significantly increased their production of total- and LL-37-positive MVs. Treatment of PBMCs or THP-1 monocytes with TSE induced the redistribution of LL-37 to the cell surface, a prerequisite for export of this molecule on membrane MVs.
Our studies indicate for the first time that extracellular LL-37 can be carried by MVs. These LL-37-positive MVs are present in skin lesions and the circulation of patients with CLE. Microvesicles in CLE can stimulate cytokine release from nearby inflammatory cells and may thereby contribute to cutaneous inflammation.
M. L. Liu,
C. O. Anyanwu,
V. P. Werth,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-proinflammatory-microvesicles-that-carry-ll-37-in-patients-with-cutaneous-lupus/