NLRP3 inflammasome activation in alveolar epithelial cells promotes myofibroblast differentiation of lung-resident mesenchymal stem cells during pulmonary fibrogenesis

2021 ◽  
Vol 1867 (5) ◽  
pp. 166077
Author(s):  
Jie Ji ◽  
Jiwei Hou ◽  
Yunhui Xia ◽  
Zou Xiang ◽  
Xiaodong Han
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Nlrp3 Inflammasome ◽  
Alveolar Epithelial Cells ◽  
Inflammasome Activation ◽  
Myofibroblast Differentiation ◽  
Alveolar Epithelial ◽  
Nlrp3 Inflammasome Activation

scholarly journals Origin of Myofibroblasts in Lung Fibrosis

2020 ◽  
Vol 1 (4) ◽  
pp. 155-162
Author(s):  
CF Hung
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Lung Fibrosis ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Lineage Tracing ◽  
Alveolar Epithelial Cells ◽  
Multiple Sources ◽  
Alveolar Epithelial

Abstract Purpose of Review In this brief review, we will highlight important observational and experimental data in the literature that address the origin of scar-forming cells in lung fibrosis. Recent Findings Several cellular sources of activated scar-forming cells (myofibroblasts) have been postulated including alveolar epithelial cells; circulating fibrocytes; and lung stromal cell subpopulations including resident fibroblasts, pericytes, and resident mesenchymal stem cells. Recent advances in lineage-tracing models, however, fail to provide experimental evidence for epithelial and fibrocyte origins of lung myofibroblasts. Resident mesenchymal cells of the lung, which include various cell types including resident fibroblasts, pericytes, and resident mesenchymal stem cells, appear to be important sources of myofibroblasts in murine models of lung injury and fibrosis. Summary Lung myofibroblasts likely originate from multiple sources of lung-resident mesenchymal cells. Their relative contributions may vary depending on the type of injury. Although lineage-tracing experiments have failed to show significant contribution from epithelial cells or fibrocytes, they may play important functional roles in myofibroblast activation through paracrine signaling.

scholarly journals Heat Shock Preconditioning Mesenchymal Stem Cells Attenuate Acute Lung Injury via Reducing NLRP3 Inflammasome Activation in Macrophages

2021 ◽  
Author(s):  
Haijin Lv ◽  
Xiaofeng Yuan ◽  
Jiebin Zhang ◽  
Tongyu Lu ◽  
Jia Yao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Pathological Changes ◽  
Nlrp3 Inflammasome Activation

Abstract Objectives: Acute lung injury (ALI) remains one of the common causes of morbidity and mortality worldwide, so far, without any effective therapeutic approach. Previous researches have revealed that topical administration of umbilical cord-derived mesenchymal stem cells (UC-MSCs) can attenuate pathological changes in experimental acute lung injury. Heat shock (HS) pretreatment has been identified as a method to enhance survival and function of cells. The present study aimed to assess whether HS-pretreated mesenchymal stem cells (MSCs) could strengthen the immunomodulation and recovery from ALI. Materials and Methods: HS pretreatment was defined 42℃ for 1h, the changes of biological characteristics and the secreted functions were detected. In the mouse model of ALI, we intranasally dripped the pretreated UC-MSCs in vivo, confirmed their therapeutic effects and detected the phenotypes of macrophages in bronchoalveolar lavage fluid (BALF). To elucidate their mechanisms, we co-cultured the pretreated UC-MSCs with macrophages in vitro, and the expression levels of inflammasome-related proteins in macrophages were assessed. Finally, Apoptozole was used for further determine the role of HSP70 in HS-pretreated UC-MSCs-based therapy. Results: The data showed that UC-MSCs did not represented significant changes in viability and biological characterizations after received HS pretreatment. Administration of HS-pretreated UC-MSCs into the ALI model, improved pathological changes and lung damage-related indexes, reduced of the levels of pro-inflammatory cytokines and modulated the balance of M1/M2. Mechanistically, both in vivo and in vitro studies demonstrated that HS pretreatment enhanced the protein level of HSP70 in UC-MSCs and subsequently upregulated the synthesis and secretion of PGE2, which negatively modulated the NLRP3 inflammasome activation of alveolar macrophages. And these effects was partially reversed by Apoptozole. Conclusion: HS pretreatment can strengthen the beneficial effects of UC-MSCs on inhibiting NLRP3 inflammasome activation of macrophages in ALI. The mechanism may be contributed to the upregulated expression of HSP70 to further induce PGE2 synthesis and secretion.

scholarly journals Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression

2019 ◽  
Vol 316 (3) ◽  
pp. L567-L577 ◽  
Author(s):  
Wu-jian Xu ◽  
Xiao-xia Wang ◽  
Jia-jia Jin ◽  
Qian Zou ◽  
Lin Wu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Mevalonate Pathway ◽  
Alveolar Epithelial Cells ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Alveolar Epithelial ◽  
Geranylgeranyl Pyrophosphate Synthase

Inhibition of the mevalonate pathway using statins has been shown to be beneficial in the treatment of acute lung injury (ALI). Here, we investigated whether partial inhibition of this pathway by targeting geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1), a catalase downstream of the mevalonate pathway, was effective at treating lung inflammation in ALI. Lipopolysaccharide (LPS) was intratracheally instilled to induce ALI in lung-specific GGPPS1-knockout and wild-type mice. Expression of GGPPS1 in lung tissues and alveolar epithelial cells was examined. The severity of lung injury and inflammation was determined in lung-specific GGPPS1 knockout and wild-type mice by measuring alveolar exudate, neutrophil infiltration, lung injury, and cell death. Change in global gene expression in response to GGPPS1 depletion was measured using mRNA microarray and verified in vivo and in vitro. We found that GGPPS1 levels increased significantly in lung tissues and alveolar epithelial cells in LPS-induced ALI mice. Compared with wild-type and simvastatin treated mice, the specific deletion of pulmonary GGPPS1 attenuated the severity of lung injury by inhibiting apoptosis of AECs. Furthermore, deletion of GGPPS1 inhibited LPS-induced inflammasome activation, in terms of IL-1β release and pyroptosis, by downregulating NLRP3 expression. Finally, downregulation of GGPPS1 reduced the membrane expression of Ras-related protein Rab10 and Toll-like receptor 4 (TLR4) and inhibited the phosphonation of IκB. This effect might be attributed to the downregulation of GGPP levels. Our results suggested that inhibition of pulmonary GGPPS1 attenuated LPS-induced ALI predominantly by suppressing the NLRP3 inflammasome through Rab10-mediated TLR4 replenishment.

scholarly journals Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xiurui Yan ◽  
Xue Fu ◽  
Yuanyuan Jia ◽  
Xiaona Ma ◽  
Jin Tao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Caspase 3 ◽  
Antioxidative Activity ◽  
A549 Cells ◽  
Oxidative Injury ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Fetal Origin

The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2-), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.

scholarly journals The Activation of NLRP3 Inflammasome Potentiates the Immunomodulatory Abilities of Mesenchymal Stem Cells in Murine Colitis Model

2020 ◽  
Author(s):  
Ji-Su Ahn ◽  
Yoojin Seo ◽  
Su-Jeong Oh ◽  
Ji Won Yang ◽  
Ye Young Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nlrp3 Inflammasome ◽  
Adult Stem Cells ◽  
In Vivo Studies ◽  
Human Umbilical Cord Blood ◽  
Inflammasome Activation ◽  
Human Umbilical Cord ◽  
Nlrp3 Inflammasome Activation

Abstract Background Inflammasomes are cytosolic, multiprotein complexes which act at the frontline of the immune responses by recognizing pathogen or danger-associated molecular patterns of pathogens or abnormal host molecules. Mesenchymal stem cells (MSCs) have been reported to possess multipotency to differentiate into various cell types and immunoregulatory effects which make them a promising treatment for regenerative medicine and immune-related diseases, respectively. However, little is known about the expression and role of the inflammasome in adult stem cells. In this study, we investigated the expression and functional regulation of NLRP3 inflammasome in human umbilical cord blood-derived MSCs (hUCB-MSCs). Methods The expression of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome was detected in hUCB-MSCs. Cell proliferation, death and differentiation were analyzed after NLRP3 inflammasome activation. To investigate the changes in immunoregulatory functions of hUCB-MSCs, naïve or NLRP3 inflammasome-stimulated cells were infused into chemically induced colitic mice and symptoms were monitored. Results NLRP3 inflammasome activation suppressed the differentiation of hUCB-MSCs into osteoblasts, which was restored when the expression of adaptor proteins for inflammasome assembly was inhibited. Moreover, the suppressive effects of MSCs on T cell responses and the macrophage activation were augmented in response to NLRP3 activation. In vivo studies using colitic mice revealed that the protective abilities of hUCB-MSCs increased after NLRP3 stimulation. Conclusions Our findings suggest that the NLRP3 inflammasome components are expressed in hUCB-MSCs and its activation can regulate the differentiation capability and the immunomodulatory effects of hUCB-MSCs.

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