Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice
Fei CaoXin-Yi TianZhongwang LiYa LvJun HanRong ZhuangBihuan ChengYuqiang GongBinyu YingShengwei JinYe Gao
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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 injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 hours later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1β (IL-1β) and IL-18 secretion, the expression of NLRP3 inflammasome components including pro-IL-1β, NLRP3 and Cleaved Caspase-1 as well as phosphorylation of NF-κB p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of JAK2 and 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 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.Keywords:
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Erythropoietin(EPO),a hematopoietic cytokine,possesses strong antiapoptotic tissue-protective properties.Recently several studies have shown that carbamylated EPO(CEPO) did not bind to the classical EPO receptor(EPOR) and did not show any hematopoietic activity.Nevertheless,CEPO showed tissue protection through its ability to bind to a new hetero-receptor complex comprising both EPOR and common β receptor(βcR) at a potency and efficacy comparable to EPO.Unlike EPO,CEPO has no effect on hematocrit.CEPO showed the antiapoptotic protective effects through its ability to limit both remodeling and the extent of the scar.
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Background: Expression of erythropoietin (Epo) is controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α). Epo signaling via erythropoietin receptor (EpoR) results in stimulation of cell proliferation and upregulation of the antiapoptotic protein bcl-2 followed by inhibition of apoptosis. Epo has previously been demonstrated to be associated with Schwann cell proliferation and a recent clinical case report suggested a role in vestibular schwannoma growth.
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Recent studies have shown that erythropoietin (EPO) and its specific receptor (EPOR) are expressed in malignant tumors, and EPO was found to promote tumor angiogenesis and proliferation, inhibit tumor cell apoptosis,or regulate sensitivity to chemoradiothrapy. moreover,several clinical researches have also shown that EPO was not associated with improved cancer control or survival. Further,preclinical experiments will have to elucidate the multiple molecular effects of EPO on tumor progression and survival in cancer patients.
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Erythropoietin; Receptors, Erythropoietin; Neoplasms
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Over the past two decades it has emerged that, in addition to erythropoietic activity, erythropoietin (EPO) has numerous other functions, including neuro-protective, anti-apoptotic, antioxidant, angiogenetic and immunomodulatory ones. EPO interacts with two different forms of its receptor (EPOR): a homodimer receptor, responsible for the erythropoietic effects, and a heterodimer receptor, responsible for the non-erythropoietic effects. The effects on the heterodimer receptor are responsible for EPO-induced prolongation of organ transplant survival in mice and humans. The development of new molecules that selectively target the heterodimer EPOR is allowing to test the effect of long-term treatments, without the possible complications related to the increased hematocrit.
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Abstract Purpose: The use of erythropoietin in head and neck squamous cell carcinoma (HNSCC) has been associated with poor survival. This study examines the protein and mRNA expression of erythropoietin and erythropoietin receptor in HNSCC and their relation to hypoxia, hemoglobin (Hb), and clinical outcome. Experimental Design: The immunohistochemical expression of erythropoietin and erythropoietin receptor was assessed in 151 cases of HNSCC. Expression was compared with the hypoxia-dependent proteins hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase-9 (CA-9) and correlated with clinical outcome. The mRNA expression of erythropoietin and erythropoietin receptor was measured in paired samples of HNSCC. Results: Erythropoietin and erythropoietin receptor were expressed in 95% and 99% of tumors, respectively. Using a weighed expression score, there was a positive correlation between erythropoietin and erythropoietin receptor expression (r = 0.18, P = 0.03). HIF-1α (r = 0.38, P < 0.01) and CA-9 (r = 0.26, P = 0.002) correlated with erythropoietin expression, but there was no correlation with erythropoietin receptor. No correlation was found between Hb and erythropoietin (r = 0.07, P = 0.36) or erythropoietin receptor (r = −0.02, P = 0.8), and no survival difference between high and low erythropoietin or erythropoietin receptor expression (P = 0.59 and P = 0.98, respectively). The mRNA expression of erythropoietin (P = 0.03) but not erythropoietin receptor (P = 0.62) was significantly increased in 11 paired samples of HNSCC. Conclusion: In vivo, the HIF pathway regulates erythropoietin at the mRNA level but not erythropoietin receptor expression in HNSCC. Anemia does not seem to influence the hypoxic microenvironment of tumors sufficiently to alter the expression of erythropoietin. The effects of exogenous erythropoietin may be acting via receptors expressed on tumor cells in vivo, or on vascular cells, which also express the pathway.
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Erythropoietin (EPO) has long been utilized for the treatment of renal anemia. The erythropoietin receptor (EPOR) is also expressed in the cardiovascular and central nervous systems in addition to an erythroid lineage, to provide an organoprotective role against several types of cellular stress. Pulmonary hypertension (PH) is a poor prognostic disease caused by primary and secondary pulmonary vascular injury. We observed the effects of EPO derivatives on monocrotaline-induced PH in rats on the supposition that EPO may protect small arteries from injury. Asialoerythropoietin (AEPO) lacks sialic acids in the termini of carbohydrate chains that results in rapid clearance from blood. Carbamyl-erythropoietin (CEPO) interacts with EPOR/βc heterodimers, but not with EPOR homodimers expressed in erythroid cells. Monocrotaline-injected rats were treated with continuous intravenous injection of 2500 ng/kg/day of EPO, AEPO, or CEPO for 21 days, and lung histology, cardiac function, and mRNA expression in the lungs were examined. Wall thickening of small arteries in the lungs and PH were improved by administration of EPO, but not by its non-hematopoietic derivatives, AEPO, or CEPO. Erythropoietin administration increased mRNA expression of the anti-apoptotic molecule, Bcl-xL, and maintained expression of the CD31 antigen. We conclude that lungs may express EPOR homoreceptors, but not heteroreceptors. Adequate serum erythropoietin levels may be essential for pulmonary protective effects.
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Introduction Erythropoietin, the Endothelium and Angiogenesis Erythropoietin and the Central Nervous System Cellular Biology of Erythropoietin in the Central Nervous System Expression of Erythropoietin and the Erythropoietin Receptor by Neuronal Cells at the Cellular Level The Neuroprotective Action of Erythropoietin Erythropoietin and the Reproductive System Erythropoietin and the Heart Erythropoietin and the Gastrointestinal System Erythropoietin and Other Cell Types Are Erythropoietin Receptors Outside of the Hematopoietic System Really Necessary? Erythropoietin and Malignancy References
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