A proposed role of neutrophil extracellular traps and their interplay with fibroblasts in ANCA-associated vasculitis lung fibrosis

Negreros, Miguel; Flores‐Suárez, Luis Felipe

doi:10.1016/j.autrev.2021.102781

Cited by 35 publications

(25 citation statements)

References 93 publications

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“…The authors also found that SARS-CoV-2 infection increases NETosis in co-cultured lung epithelial cells, macrophages, and neutrophils, as evidenced by increased SMA (a mesenchymal marker) expression and decreased E-cadherin (an epithelial marker) expression. Other studies reported that NETs and NET-associated proteins favor the expression of inflammatory and fibrotic genes ( 107 ), or increase the number and activity of fibroblasts ( 108 ) in ex-COVID-19 fibrosis induced by chemical or infectious stimuli. These data may indirectly implicate NETs as important players in the pathogenesis of pulmonary fibrosis post COVID-19.…”

Section: Netosis and Nets In The Pathology Of Covid-19 Beyond Immunot...mentioning

confidence: 99%

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

2022

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Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.

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Section: Netosis and Nets In The Pathology Of Covid-19 Beyond Immunot...mentioning

confidence: 99%

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

2022

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“…More specifically, in ANCA-associated ILD, a direct role of MPO antibodies in the pathogenesis of pulmonary fibrosis has been implied [33]. In vitro activation of MPO by anti-MPO antibodies has been shown to lead to the production of oxidant products including hypochlorous acid, triggering fibroblast proliferation and extracellular matrix deposition in the distal pulmonary parenchyma [54][55][56] (figure 1 [19,57]). Furthermore, FOUCHER et al [55] observed patchy inflammatory cell infiltrates throughout the parenchyma of the lung in their MPO-induced rat model of AAV, suggesting that the presence of MPO antibodies trigger an autoimmune response including activation of neutrophils.…”

Section: Pathogenesis Of Aav-ildmentioning

confidence: 99%

“…Furthermore, FOUCHER et al [55] observed patchy inflammatory cell infiltrates throughout the parenchyma of the lung in their MPO-induced rat model of AAV, suggesting that the presence of MPO antibodies trigger an autoimmune response including activation of neutrophils. ANCA-activated neutrophils locally release proteolytic enzymes such as elastase or neutrophil extracellular traps (NETs), contributing to pulmonary tissue injury and fibrosis [55,56]. Though the exact mechanisms remain unknown, NETs have been shown to play an important role in the pathogenesis of AAV [56].…”

Section: Pathogenesis Of Aav-ildmentioning

confidence: 99%

“…ANCA-activated neutrophils locally release proteolytic enzymes such as elastase or neutrophil extracellular traps (NETs), contributing to pulmonary tissue injury and fibrosis [55,56]. Though the exact mechanisms remain unknown, NETs have been shown to play an important role in the pathogenesis of AAV [56]. Patients with active AAV express higher levels of circulating NET remnants when compared to patients in remission [58,59].…”

Section: Pathogenesis Of Aav-ildmentioning

confidence: 99%

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Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review

Kadura

Raghu

2021

Eur Respir Rev

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Over the past three decades, an increasing number of publications have reported the association between interstitial lung disease (ILD) and anti-neutrophil cytoplasmic antibody (ANCA) or ANCA-associated vasculitis (AAV). With this increased awareness, we have reviewed the literature to date and provide an update in this narrative review. The vast majority of cases of ILD have been shown to be in the setting of positive anti-myeloperoxidase antibody and can be present in up to 45% of patients of microscopic polyangiitis, though cases of ILD associated with proteinase 3 ANCA have rarely been reported. Pulmonary fibrosis and ANCA positivity can occur with or without systemic involvement. The pathogenetic mechanisms establishing the relationship between ANCA and the development of pulmonary fibrosis remain unclear. Histologic and radiographic features of ANCA-ILD most commonly reveal usual interstitial pneumonia or non-specific interstitial pneumonia patterns, though other atypical features such as bronchiolitis have been described. ILD in the setting of AAV has been associated with worse outcomes, and thus early identification and treatment in these patients is appropriate. We advocate that ANCA antibody testing be performed as a baseline evaluation in patients presenting with idiopathic interstitial pneumonia. Suggested treatment of ANCA-ILD includes immunosuppression and/or antifibrotic agents, though supporting data and clinical trials to substantiate use of these therapies are needed.

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“…Although a lid biopsy was not allowed due to Ethic Board regulations in our case, the clinical course and improvement of ocular findings only after systemic steroid use suggest an association with GPA. In ANCA-associated vasculitis, neutrophil extracellular traps (NETs), a bactericidal mechanism of neutrophils, have been shown to promote myeloperoxidase-ANCA production, thrombosis, inflammation and fibrosis, leading to a vicious cycle of inflammatory tissue changes [44][45][46][47]. In a recent study, NETs were found in the ocular discharge of patients with blepharitis, and extensive aggregation of NETs were found in the meibomian glands [48].…”

Section: Discussionmentioning

confidence: 99%

Atypical Granulomatosis with Polyangiitis Presenting with Meibomitis, Scleritis, Uveitis and Papillary Bladder Tumor: A Case Report and Literature Review

et al. 2021

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Granulomatosis with polyangiitis (GPA) presents with a variety of systemic findings, sometimes with ocular findings initially, but is often difficult to diagnose at an early stage. An 85-year-old male had complaints of ocular dryness and redness and was diagnosed with meibomian gland dysfunction with meibomitis. Despite an initial treatment with topical steroid and antibiotics, the meibomitis did not improve and the left eye developed scleritis and iridocyclitis. The patient was administered topical mydriatics and oral steroids. During follow-up, the patient developed left hearing difficulty and reported a darker urine. Urinalysis revealed microscopic hematuria. A blood test showed an elevated erythrocyte sedimentation rate, positivity for perinuclear anti-neutorophil cytoplasmic antibody, and elevations in blood urea nitrogen and serum creatinine. Nasal mucosal biopsy showed a non-necrotizing granulomatous inflammation. Renal biopsy revealed focal glomerulosclerosis. Cystoscopy and bladder wash followed by a planned transurethral resection revealed atypical cells and apical papillary tumors which were resected. Iridocyclitis and scleritis responded well to oral prednisolone with 0.1% topical betamethasone and prednisolone ointment. The patient is tumor free with no recurrences 24 months after resection. GPA may present atypically with meibomian gland dysfunction without showing representative clinical findings. Early detection and treatment are essential for visual recovery.

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A proposed role of neutrophil extracellular traps and their interplay with fibroblasts in ANCA-associated vasculitis lung fibrosis

Cited by 35 publications

References 93 publications

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

Antineutrophil cytoplasmic antibody-associated interstitial lung disease: a review

Atypical Granulomatosis with Polyangiitis Presenting with Meibomitis, Scleritis, Uveitis and Papillary Bladder Tumor: A Case Report and Literature Review

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