N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro

• Published in: International journal of molecular sciences 2022-11, Vol.23 (23), p.14518
• Main Authors: Milara, Javier, Martínez-Expósito, Fernando, Montero, Paula, Roger, Inés, Bayarri, Maria Amparo, Ribera, Pilar, Oishi-Konari, Miriam Natsuki, Alba-García, Jose Ramón, Zapater, Enrique, Cortijo, Julio
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Biopsy; Cell activation; Coronaviruses; COVID-19; COVID-19 vaccines; Cytokines; Disease control; Epithelial cells; Epithelium; Gene expression; Humans; Immune response; Immunohistochemistry; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Innate immunity; Kinases; Macrophages; MyD88 protein; N-acetylcysteine; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NOX4 protein; Pandemics; Proteins; Recombinant Proteins - pharmacology; Respiration; Respiratory diseases; SARS-CoV-2; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; TLR2 protein; Toll-like receptors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232314518

Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, = 32), SARS-CoV-2 B.1 variant ( = 31), and B.1.1.7 VOC alpha variant ( = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.