Role of complement in modulation of TH2 response in prostate cancer cells

Yamamoto, Haruyasu; Fara, Antonella Maria; Chandra, Ashish; Cardone, John; Kemper, Claudia

doi:10.1016/j.imbio.2012.08.204

Cited by 1 publication

(1 citation statement)

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“…Complement inhibitors (eg, AMY-101, eculizumab, or its variant ravulizumab) are currently in advanced stages of SARS-CoV-2 clinical trials and can be administered to the lungs through nebulizers. [47][48][49] Beside anaphylatoxin targeting, another yet unexplored option is the targeting of regulators of complement activation such as CD46 or CD55 in the lungs of patients with COVID-19 to reduce inflammation. 48,50 As illustrated herein and also reviewed in Jodele and Koehl, 7 complement may serve as a powerful new therapeutic target for COVID-19 treatment, because severely ill patients with COVID-19 with atypical ARDS showed an extensive complement activation both systemically and within the lungs.…”

Section: Discussionmentioning

confidence: 99%

C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia

Posch

Vosper

Noureen

et al. 2021

Journal of Allergy and Clinical Immunology

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Background Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe SARS-CoV-2 infections and is associated with enhanced pathogenicity and mortality. Objective Complement hyper activation promotes lung injury and was observed in patients suffering from MERS-CoV, SARS-CoV-1 and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells upon exposure to SARS-CoV-2 in terms of complement C3-mediated effects. Methods For this, we used highly differentiated primary human 3D tissue models infected with SARS-CoV-2 patient isolates. Upon infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses and TEER measurements. Results Here we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2-infected 3D cultures secreted significantly higher levels of C3a and the pro-inflammatory cytokines IL-6, MCP-1, IL-1α and RANTES. Conclusion Crucially, we illustrate here for the first time, that targeting the anaphylotoxin receptors C3aR and C5aR in non-immune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19.

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