Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. An excessive inflammatory response results in the progression of ALI/ARDS, and the NLRP3 inflammasome is a key participant in inflammation. Erythropoietin (EPO), which is clinically used for anemia, reportedly exerts pleiotropic effects in ALI. However, whether EPO could protect against lipopolysaccharide (LPS)-induced ALI by regulating the NLRP3 inflammasome and its underlying mechanisms remain poorly elucidated. This study aimed to explore whether the therapeutic effects of EPO rely on the suppression of the NLRP3 inflammasome and the specific mechanisms in an LPS-induced ALI mouse model. ALI was induced in C57BL/6 mice by intraperitoneal (i.p.) injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 h later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry (W/D) ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1β (IL-1β) and interleukin-18 (IL-18) secretion, the expression of NLRP3 inflammasome components including pro-IL-1β, NLRP3, and cleaved caspase-1 as well as phosphorylation of nuclear factor-κB (NF-κB) p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of Janus-tyrosine kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). However, all the beneficial effects of EPO on ALI and modulation NLRP3 inflammasome were remarkably abrogated by the inhibition of EPOR/JAK2/STAT3 pathway and knockout (KO) of NLRP3 gene. Taken together, this study indicates that EPO can effectively attenuate LPS-induced lung injury in mice by suppressing the NLRP3 inflammasome, which is dependent upon activation of EPOR/JAK2/STAT3 signaling and inhibition of the NF-κB pathway.

Erythropoietin Ameliorates Ischemia/Reperfusion-Induced Acute Kidney Injury via Inflammasome Suppression in Mice

“…Secondly, NLRP3 among inflammasome components is well known to various kidney disease including IR-AKI. The protective effect of EPO on AKI is very well-described; however, it is not for inflammasome, even reported in acute lung injury [34]. According to our data, EPO significantly decreased the expression levels of the inflammasome-related factors NLRP1, NLRP3, and cleaved caspase-1.…”

Comprehensive Analysis of LncRNA-mRNA Expression Profiles and the ceRNA Network Associated with Pyroptosis in LPS-Induced Acute Lung Injury

“…We used siRNA-lncRNA4344 and observed that interference with lncRNA4344 increased the expression of NLRP3 and LPS-induced IL-18 and IL-1β production, which is considered a critical role in early ALI. 35 , 36 Western Blot results also confirmed the NLRP3 and Caspase-1 expression levels were decreased under siRNA-lncRNA4344 conditions. We proposed that therapy targeting lncRNAs related to ceRNA regulatory mechanisms may provide a different direction for ALI/ARDS treatment.…”

Severe COVID-19: NLRP3 Inflammasome Dysregulated

“…The first clinical study for a NLRP3 inflammasome inhibitor (Tranilast) to treat COVID-19 is ongoing and registered in the Chinese clinical trial registry ( 45 ). Other studies are still in a pre-clinical phase and study the effect on acute lung injury or on cell lines for example with resveratrol ( 46 ), tetracycline ( 47 ) or erythropoietin ( 48 ) or nicardipine, a L-type calcium antagonist ( 49 ), lidocaine ( 50 ) CP-456,773 ( 51 ), Diacerein ( 52 ). For colchicine it is hypothesized that it has an effect on NLRP3-mediated diseases ( 53 ).…”