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Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.

ABSTRACT: Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-? and further promoted the development of IL-10- and TGF-?-secreting CD4⁺ T cells. Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis.

SUBMITTER: Popat RJ

PROVIDER: S-EPMC5256146 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.

Popat Reena J RJ Hakki Seran S Thakker Alpesh A Coughlan Alice M AM Watson Julie J Little Mark A MA Spickett Corinne M CM Lavender Paul P Afzali Behdad B Kemper Claudia C Robson Michael G MG

JCI insight 20170126 2

Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion ...[more]

PMID: 28138552

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Project description:IntroductionIncreasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.MethodsSix recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.ResultsCompared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P?=?0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P?=?0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P?<?0.001; 41.2% versus 14.1%, P?=?0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P?=?0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P?<?0.001].ConclusionsLinear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.

Project description:Saccharomyces cerevisiae is a single-celled fungal microorganism. S. cerevisiae-derived vacuoles are closely related to mammalian lysosomes, which play a role in the degradation of macromolecules by various hydrolytic enzymes. This study evaluated the anti-inflammatory efficacy of S. cerevisiae-vacuoles by inhibiting inflammatory mediators induced by lipopolysaccharide (LPS). The results showed that treatment with 5, 10, and 20 µg/mL of S. cerevisiae-derived vacuoles almost completely inhibited the LPS-induced expression of iNOS protein and mRNA. Moreover, vacuoles significantly reduced the mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) in LPS-stimulated macrophages compared to the control cells. The immunofluorescence analysis confirmed that S. cerevisiae-derived vacuoles inhibited the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated cells. Taken together, the treatment with S. cerevisiae-derived vacuoles alone activated macrophages, but LPS-activated macrophages modulated pro-inflammatory mediators by downregulating the NF-κB pathway. These results suggest that S. cerevisiae-derived vacuoles may have therapeutic potential in the treatment of inflammatory diseases. In conclusion, our study provides new insights into the immunomodulatory effects of S. cerevisiae-derived vacuoles and their potential as a novel anti-inflammatory agent. IMPORTANCE This study investigates the potential of using vacuoles derived from the yeast Saccharomyces cerevisiae as a new anti-inflammatory therapy. Inflammation is a natural response of the immune system to invading pathogens, but when it is dysregulated, it can lead to chronic diseases. The researchers found that treating macrophages with vacuoles significantly reduced the production of pro-inflammatory cytokines and iNOS, markers of inflammation when they were stimulated with lipopolysaccharide. The study also showed that vacuoles inhibited the NF-κB signaling pathway, which is involved in the induction of pro-inflammatory cytokines in macrophages. These findings suggest that S. cerevisiae-derived vacuoles may have potential as a new therapeutic agent for regulating the inflammatory response in various diseases. Further studies are needed to evaluate the efficacy and safety of vacuoles in vivo and to elucidate the underlying mechanisms of their anti-inflammatory effects.

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Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.

Publications

Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.

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