Ubiquitination in NETs May Affect Adaptive Immune Responses in SLE

Neutrophil extracellular traps (NETs) contain ubiquitinated proteins with a lower expression of polyubiquitinated proteins in individuals with systemic lupus erythematosus (SLE), according to the results of a study published in the Annals of Rheumatic Diseases.

Ana Barrera-Vargas, MD, from the Department of Immunology and Rheumatology, National Institute of Medical Sciences and Nutrition, Mexico City, Mexico, and colleagues studied 74 patients with SLE and 77 healthy control patients. Ubiquitin content was quantified in NETs by western blot analysis, enzyme-linked immunosorbent assay, and immunofluorescence microscopy, whereas ubiquitination of NET proteins was assessed by immunoprecipitation. Monocyte-derived macrophages from individuals with SLE and control patients were isolated and stimulated with NETs or ubiquitin. After these stimuli, calcium flux and cytokine synthesis were measured.

The results showed that myeloperoxidase is present in ubiquitinated form in NETs. In addition, patients with SLE develop an antiubiquitinated form in NETs, and titers of these correlate positively with Systemic Lupus Erythematosus Disease Activity Index scores (P <.01) and correlate negatively with complement components (P <.01). In this study, stimulation of monocyte-derived macrophages with NETs or ubiquitin resulted in enhanced calcium flux, and stimulation with NETs increased the production of tumor necrosis factor-alpha and interleukin 10 in macrophages from patients with SLE compared with control patients.

The authors note that this is the first study to demonstrate the presence of polyubiquitinated proteins in NETs, with a differential profile between patients with SLE and healthy control patients. The data suggest that ubiquitinated myeloperoxidase in NETs is a target of humoral responses in SLE. They add that ubiquitin present in NETs is one of the components that regulates calcium flux in macrophages, and that lupus macrophages synthesize inflammatory cytokines as a reaction to NET internalization.

Overall, the authors argue that abnormalities in mechanisms involved in NET internalization and the extracellular ubiquitination pathway may play important roles in the inflammatory responses in SLE.

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Reference

Barrera-Vargas An, Gomez-Martin D, Carmona-Rivera C, et al. Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus [published online March 27, 2018]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2017-212617