Exosomal miRNAs targeting NLRP3 inflammasome platform are associated with radiologic sequelae in survivors of COVID-19-associated acute respiratory distress syndrome

Background: There is limited understanding of the pathophysiology of post-acute pulmonary sequelae in COVID-19-associated acute respiratory distress syndrome (ARDS). We aimed at investigating the association of circulating microRNAs (miRNAs) involved in post-transcriptional regulation of NLRP3-inflammasome pathways and lung radiological features among COVID-19- associated ARDS survivors. Methods: We evaluated COVID-19-associated ARDS survivors at 4±2 months from clinical recovery. Patients were selected based on imaging pattern evolution according to chest high-resolution computerized tomography (HRCT) findings into “fully recovered” (FR), “pulmonary opacities” (PO) and “fibrosis-like lesions” (FL) according to radiological appearance. Plasma miRNA profiling was performed using real time quantitative polymerase chain reaction (RT-qPCR). The exosomal expression of NLRP3 inflammasome related miRNAs (miR-17-5p, miR-223-3p, miR-146a-5p) was evaluated. Results: 31 patients (33% men, mean age 60±6 years, mean BMI 31.1±6.6 Kg/m2) were selected for the present study. No statistically significant differences between FR, PO and FL patterns were observed according to clinical features. NLRP3-inflammasome-related miRNAs such as miR-17-5p, miR-223-3p and miR-146a-5p were significantly up-regulated in patients with PO when compared to patients with FL. miR-146a-5p was also up-regulated in patients with FL than in FR. Conclusions: In patients with long-term pulmonary radiological sequelae following COVID71 19- associated ARDS, a down-regulation of miRNAs inhibiting NLRP3 (miR-17-5p, miR-146a72 3p and miR-223-3p) correlated to fibrosis development in patients showing persistent hyper-reactivity to inflammatory stimulation. NLRP3-Inflammasome-related miRNAs could be a possible therapeutic target to prevent the fibrotic evolution of COVID-19-associated ARDS.