Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus

Barrera‐Vargas, Ana; Gómez‐Martín, Diana; Carmona‐Rivera, Carmelo; Merayo-Chalico, Javier; Torres-Ruíz, Jiram; Manna, Zerai; Alcocer‐Varela, Jorge; Kaplan, Mariana J.

doi:10.1136/annrheumdis-2017-212617

Cited by 45 publications

(63 citation statements)

References 53 publications

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“…Barrera-Vargas et al (60) reported, as the current study was underway, that stimulation with LPS-induced NETs led to an enhanced production of TNF-a and IL-10 in macrophages from patients with SLE when compared with controls, and this was dampened when macrophages were treated with chloroquine, an inhibitor of endosomal acidification and lysosomal enzyme activity. Because acidic pH of endosomes is a prerequisite of endosomal TLR activation, chloroquine is frequently used as an antagonist for endosomal TLRs, and the results thus suggest that TLR signaling is partly implicated (60). Moreover, these findings underscore that responses to NETs in healthy individuals and in patients with autoimmune diseases may differ.…”

Section: Discussionmentioning

confidence: 48%

Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells

Lazzaretto

Fadeel

2019

The Journal of Immunology

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Neutrophil extracellular traps (NETs) composed of nuclear DNA associated with histones and granule proteins are involved in the extracellular killing of pathogens. Excessive NET formation has been implicated in several noninfectious pathological conditions. The disposal of NETs is, therefore, important to prevent inadvertent effects resulting from the continued presence of NETs in the extracellular environment. In this study, we investigated the interaction of NETs released by freshly isolated, PMA-stimulated primary human neutrophils with primary human monocyte–derived macrophages or dendritic cells (DCs). NETs were internalized by macrophages, and removal of the protein component prevented engulfment of NETs, whereas complexation with LL-37 restored the uptake of “naked” (protein-free) NETs. NETs were also found to dampen the bacterial LPS-induced maturation of DCs. Cytokine profiling was conducted by using a multiplex array following the interaction of NETs with macrophages or DCs, and NETs alone were found to be noninflammatory, whereas immunomodulatory effects were noted in the presence of LPS with significant upregulation of IL-1β secretion, and a marked suppression of other LPS-induced factors including vascular endothelial growth factor (VEGF) in both cell types. Moreover, macrophage digestion of NETs was dependent on TREX1 (also known as DNaseIII), but not DNaseII, whereas extracellular DNase1L3-mediated degradation of NETs was observed for DCs. Collectively, these findings shed light on the interactions between NETs and phagocytic cells and provide new insights regarding the clearance of NETs, double-edged swords of innate immunity.

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Section: Discussionmentioning

confidence: 48%

Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells

Lazzaretto

Fadeel

2019

The Journal of Immunology

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“…Less clear, and worth of further investigation, is the contribution of cit-LL37 to the immunogenicity of LL37 in psoriasis, a disease characterized by decreased citrullinated proteins in hyperproliferative epidermis, but also by neutrophil infiltrate 61 . Also, we are aware that the role of citrullination in autoreactivity in SLE could be restricted to the LL37-directed response, as additional post-translational modifications are reasonably considered dominant in SLE 62 . Of interest for the rheumatology field, the correlation between T-cell responses and antibody levels, and of both responses with disease activity (SLEDAI), renders LL37-directed responses interesting biomarkers, at least in patients that respond to LL37.…”

Section: Discussionmentioning

confidence: 99%

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Lande

Palazzo

Gestermann

et al. 2020

Sci Rep

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LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(T fH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications. Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20-50 cases per 100,000 in Northern Europe and USA 1 , characterized by immune-complex formation and deposition, which result in inflammation and tissue damage. In SLE, altered clearance of dying cells determines persistent exposure of autoantigens and activation of antigen-presenting cells (APCs), mainly via Toll-like receptors (TLR), thus favoring adaptive immune response licensing 1-3. SLE autoantibodies are preferentially directed against

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“…Nonetheless, the main pathogenic role of LDNs/LDGs in autoimmunity appears to be largely related to their enhanced ability, relative to autologous NDNs, to expose autoantigens through the release of NETs [96]. In this context, NETs released by LDNs/LDGs obtained from the peripheral blood of SLE patients contain, compared with NETs from autologous or healthy control circulating NDNs, elevated amounts of immunogenic antigens such as oxidized mitochondrial DNA [103] and citrullinated or ubiquitinated antigens that can activate plasmacytoid dendritic cells or macrophages [96,104]. Moreover, in RA patients, NET-derived citrullinated antigens from circulating neutrophils have been recently found to be phagocytosed and presented to in vitro generated antigen-specific CD4 + T cell clones by synovial fibroblasts, which in turn can trigger the generation of autoantibodies that contribute to inflammation [105].…”

Section: Neutrophil Diversity and Heterogeneity In Chronic Inflammationmentioning

confidence: 99%

Neutrophil Diversity in Health and Disease

Silvestre-Roig

Fridlender

Glogauer

et al. 2019

Trends in Immunology

376

335

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Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus

Cited by 45 publications

References 53 publications

Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells

Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Neutrophil Diversity in Health and Disease

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