Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury

Abstract

MicroRNA (miRNA) mediates RNA interference to regulate a variety of innate immune processes, but how miRNAs coordinate the mechanisms underlying acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with pulmonary inflammatory injury is still unknown. In this study, we demonstrated that miR-223 limits the number of Ly6G+ neutrophils and inhibits the activity of the NLRP3 inflammasome to alleviate ALI induced by mitochondrial damage-associated molecular patterns (DAMPs) (MTDs). miR-223 expression is increased in the lungs of MTD-induced mice or ARDS patients following trauma/transfusion or following the physiological remission of ALI/ARDS. miR-223−/+ mice exhibited more severe ALI and cytokine dysregulation. Other studies have shown that MTD-induced increases in miR-223 expression are mainly contributed by Ly6G+ neutrophils from the haematopoietic system. miR-223 blocks bone marrow-derived Ly6G+ neutrophil differentiation and inhibits peripheral cytokine release. In addition, MTD-induced miR-223 expression activates a negative feedback pathway that targets the inhibition of NLRP3 expression and IL-1β release; therefore, miR-223 deficiency can lead to the sustained activation of NLRP3-IL-1β. Finally, elimination of peripheral Ly6G+ neutrophils and pharmacological blockade of the miR-223–NLRP3–IL-1β signalling axis could alleviate MTD-induced ALI. In summary, miR-223 is essential for regulating the pathogenesis of DAMP-induced ALI.

Scutellaria barbata D. Don (SBD) protects oxygen glucose deprivation/reperfusion-induced injuries of PC12 cells by up-regulating Nrf2

“…PI3K/AKT pathway plays an important biological role in cell apoptosis, survival, proliferation, cytoskeleton change and other biological processes [32]. It has been proved that the PI3K/AKT signalling pathway participates in the regulation of the pathological process of cerebral ischemia injury [33][34][35]. In addition, several studies have reported that Nrf2 is a downstream regulator of PI3K/AKT pathway [18,36].…”

Immediate and long-term consequences of COVID-19 infections for the development of neurological disease

“…Evidence from murine lung injury models and ARDS patient samples emphasize the role of the NLRP3 inflammasome in the pathogenesis and detrimental outcome of ARDS [20,21]. In keeping with this, the coronavirus ORF3a protein has been shown to induce NLRP3 inflammasome activity [22].…”

MicroRNA miR-223 as regulator of innate immunity

“…Furthermore, miR‐223 is expressed stably at high levels in neutrophils and overexpression of miR‐223 was shown to diminish NLR family pyrin domain containing 3 (NLRP3) inflammasome activity via direct targeting of NLRP3 and in turn dampens NLRP3‐dependent IL‐1β production . The NLRP3‐miR‐223 axis was further studied in acute lung injury (ALI) . Patients with acute respiratory distress syndrome (ARDS) caused by trauma and blood transfusion showed high level of miR‐223 in the bronchial alveolar lavage fluid (BALF) when compared with health controls.…”

“…49 The NLRP3-miR-223 axis was further studied in acute lung injury (ALI). 50 Patients with acute respiratory distress syndrome (ARDS) caused by trauma and blood transfusion showed high level of miR-223 in the bronchial alveolar lavage fluid (BALF) when compared with health controls. In ALI induced by mitochondrial damage-associated molecular patterns (DAMPs) (MTDs), miR-223 −/+ mice experienced decreased arterial oxygen partial pressure to fractional inspired oxygen ratio (PaO 2 /FiO 2 ), increased lung wet to dry ratio, and elevated infiltrating cells to the airway.…”