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Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates.

ABSTRACT: Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many infectious diseases, yet their dynamics and impact on HIV/SIV infection have not yet been assessed. We hypothesized that SIV infection and the related microbial translocation trigger NET activation and release (NETosis), and we investigated the interactions between NETs and immune cell populations and platelets. We compared and contrasted the levels of NETs between SIV-uninfected, SIV-infected, and SIV-infected antiretroviral-treated nonhuman primates. We also cocultured neutrophils from these animals with either peripheral blood mononuclear cells or platelets. Increased NET production was observed throughout SIV infection. In chronically infected animals, NETs were found in the gut, lung, and liver, and in the blood vessels of kidney and heart. Antiretroviral therapy (ART) decreased NETosis, albeit above preinfection levels. NETs captured CD4+ and CD8+ T cells, B cells, and monocytes, irrespective of their infection status, potentially contributing to the indiscriminate generalized immune cell loss characteristic to HIV/SIV infection, and limiting the CD4+ T cell recovery under ART. By capturing and facilitating aggregation of platelets, and through expression of increased tissue factor levels, NETs may also enhance HIV/SIV-related coagulopathy and promote cardiovascular comorbidities.

SUBMITTER: Sivanandham R

PROVIDER: S-EPMC6205390 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates.

Sivanandham Ranjit R Sivanandham Ranjit R Brocca-Cofano Egidio E Krampe Noah N Falwell Elizabeth E Venkatraman Sindhuja Murali Kilapandal SMK Ribeiro Ruy M RM Apetrei Cristian C Pandrea Ivona I

The Journal of clinical investigation 20181015 11

Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many infectious diseases, yet their dynamics and impact on HIV/SIV infection have not yet been assessed. We hypothesized that SIV infection and the related microbial translocation trigger NET activation and release (NETosis), and we investigated the interactions between NETs and immune cell populations and platelets. We compared and contrasted the levels of NETs between SIV-uninfected, SIV-infected, and SIV-infected antire ...[more]

PMID: 30204591

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Project description:Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis is a systemic small-vessel vasculitis, wherein, MPO-ANCA plays a critical role in the pathogenesis. Neutrophil extracellular traps (NETs) released from activated neutrophils are composed of extracellular web-like DNA and antimicrobial proteins, including MPO. Diverse stimuli, such as phorbol myristate acetate (PMA) and ligands of toll-like receptors (TLR), induce NETs. Although TLR-mediated NET formation can occur with preservation of living neutrophilic functions (called vital NETosis), PMA-stimulated neutrophils undergo cell death with NET formation (called suicidal NETosis). In the process of suicidal NETosis, histones are citrullinated by peptidylarginine deiminase 4 (PAD4). Since this step is necessary for decondensation of DNA, PAD4 plays a pivotal role in suicidal NETosis. Although NETs are essential for elimination of microorganisms, excessive formation of NETs has been suggested to be implicated in MPO-ANCA production. This study aimed to determine if pan-PAD inhibitors could suppress MPO-ANCA production in vivo. At first, NETs were induced in peripheral blood neutrophils derived from healthy donors (1?×?10(6)/ml) by stimulation with 20?nM PMA with or without 20??M propylthiouracil (PTU), an anti-thyroid drug. We then determined that the in vitro NET formation was inhibited completely by 200??M Cl-amidine, a pan-PAD inhibitor. Next, we established mouse models with MPO-ANCA production. BALB/c mice were given intraperitoneal (i.p.) injection of PMA (50?ng at days 0 and 7) and oral PTU (2.5?mg/day) for 2?weeks. These mice were divided into two groups; the first group was given daily i.p. injection of PBS (200??l/day) (n?=?13) and the other group with daily i.p. injection of Cl-amidine (0.3?mg/200??l PBS/day) (n?=?7). Two weeks later, citrullination as an indicator of NET formation in the peritoneum and serum MPO-ANCA titer was compared between the two groups. Results demonstrated that citrullination in the peritoneum was significantly reduced in the Cl-amidine-treated mice compared with the vehicle-injected control mice (38% reduction). Additionally, the serum MPO-ANCA titer of the Cl-amidine-treated mice (32.3?±?31.0?ng/ml) was significantly lower than that in the vehicle-injected mice (132.1?±?41.6?ng/ml). The collective findings indicate that excessive formation of NETs may be implicated in MPO-ANCA production in vivo.

Dataset Information

Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates.

Publications

Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates.

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