Pub Date : 2024-05-11DOI: 10.1186/s13578-024-01246-0
Jiseo Song, Hyo Kyeong Kim, Hyunsoo Cho, Suh Jin Yoon, Jihae Lim, Kyunglim Lee, Eun Sook Hwang
Background: Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis.
Results: Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ.
Conclusions: Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability.
{"title":"TAZ deficiency exacerbates psoriatic pathogenesis by increasing the histamine-releasing factor.","authors":"Jiseo Song, Hyo Kyeong Kim, Hyunsoo Cho, Suh Jin Yoon, Jihae Lim, Kyunglim Lee, Eun Sook Hwang","doi":"10.1186/s13578-024-01246-0","DOIUrl":"10.1186/s13578-024-01246-0","url":null,"abstract":"<p><strong>Background: </strong>Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis.</p><p><strong>Results: </strong>Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ.</p><p><strong>Conclusions: </strong>Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"60"},"PeriodicalIF":7.5,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-09DOI: 10.1186/s13578-024-01236-2
Yuxin Sun, Mengyu Hao, Hao Wu, Chengzhi Zhang, Dong Wei, Siyu Li, Zongming Song, Ye Tao
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases that play a crucial role in the Ca2+-dependent signaling pathways. Its significance as an intracellular Ca2+ sensor has garnered abundant research interest in the domain of neurodegeneration. Accumulating evidences suggest that CaMKII is implicated in the pathology of degenerative retinopathies such as diabetic retinopathy (DR), age-related macular degeneration (AMD), retinitis pigmentosa (RP) and glaucoma optic neuropathy. CaMKII can induce the aberrant proliferation of retinal blood vessels, influence the synaptic signaling, and exert dual effects on the survival of retinal ganglion cells and pigment epithelial cells. Researchers have put forth multiple therapeutic agents, encompassing small molecules, peptides, and nucleotides that possess the capability to modulate CaMKII activity. Due to its broad range isoforms and splice variants therapeutic strategies seek to inhibit specifically the CaMKII are confronted with considerable challenges. Therefore, it becomes crucial to discern the detrimental and advantageous aspects of CaMKII, thereby facilitating the development of efficacious treatment. In this review, we summarize recent research findings on the cellular and molecular biology of CaMKII, with special emphasis on its metabolic and regulatory mechanisms. We delve into the involvement of CaMKII in the retinal signal transduction pathways and discuss the correlation between CaMKII and calcium overload. Furthermore, we elaborate the therapeutic trials targeting CaMKII, and introduce recent developments in the zone of CaMKII inhibitors. These findings would enrich our knowledge of CaMKII, and shed light on the development of a therapeutic target for degenerative retinopathy.
{"title":"Unveiling the role of CaMKII in retinal degeneration: from biological mechanism to therapeutic strategies.","authors":"Yuxin Sun, Mengyu Hao, Hao Wu, Chengzhi Zhang, Dong Wei, Siyu Li, Zongming Song, Ye Tao","doi":"10.1186/s13578-024-01236-2","DOIUrl":"10.1186/s13578-024-01236-2","url":null,"abstract":"<p><p>Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases that play a crucial role in the Ca<sup>2+</sup>-dependent signaling pathways. Its significance as an intracellular Ca<sup>2+</sup> sensor has garnered abundant research interest in the domain of neurodegeneration. Accumulating evidences suggest that CaMKII is implicated in the pathology of degenerative retinopathies such as diabetic retinopathy (DR), age-related macular degeneration (AMD), retinitis pigmentosa (RP) and glaucoma optic neuropathy. CaMKII can induce the aberrant proliferation of retinal blood vessels, influence the synaptic signaling, and exert dual effects on the survival of retinal ganglion cells and pigment epithelial cells. Researchers have put forth multiple therapeutic agents, encompassing small molecules, peptides, and nucleotides that possess the capability to modulate CaMKII activity. Due to its broad range isoforms and splice variants therapeutic strategies seek to inhibit specifically the CaMKII are confronted with considerable challenges. Therefore, it becomes crucial to discern the detrimental and advantageous aspects of CaMKII, thereby facilitating the development of efficacious treatment. In this review, we summarize recent research findings on the cellular and molecular biology of CaMKII, with special emphasis on its metabolic and regulatory mechanisms. We delve into the involvement of CaMKII in the retinal signal transduction pathways and discuss the correlation between CaMKII and calcium overload. Furthermore, we elaborate the therapeutic trials targeting CaMKII, and introduce recent developments in the zone of CaMKII inhibitors. These findings would enrich our knowledge of CaMKII, and shed light on the development of a therapeutic target for degenerative retinopathy.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"59"},"PeriodicalIF":7.5,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11084033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1186/s13578-024-01242-4
Cheng An, Zhen Li, Yao Chen, Shaojun Huang, Fan Yang, Ying Hu, Tao Xu, Chengxin Zhang, Shenglin Ge
The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, an important component of the innate immune system, is involved in the development of several diseases. Ectopic DNA-induced inflammatory responses are involved in several pathological processes. Repeated damage to tissues and metabolic organelles releases a large number of damage-associated molecular patterns (mitochondrial DNA, nuclear DNA, and exogenous DNA). The DNA fragments released into the cytoplasm are sensed by the sensor cGAS to initiate immune responses through the bridging protein STING. Many recent studies have revealed a regulatory role of the cGAS-STING signaling pathway in cardiovascular diseases (CVDs) such as myocardial infarction, heart failure, atherosclerosis, and aortic dissection/aneurysm. Furthermore, increasing evidence suggests that inhibiting the cGAS-STING signaling pathway can significantly inhibit myocardial hypertrophy and inflammatory cell infiltration. Therefore, this review is intended to identify risk factors for activating the cGAS-STING pathway to reduce risks and to simultaneously further elucidate the biological function of this pathway in the cardiovascular field, as well as its potential as a therapeutic target.
环鸟苷单磷酸（GMP）-腺苷单磷酸（AMP）合成酶-干扰素基因刺激器（cGAS-STING）信号通路是先天性免疫系统的重要组成部分，与多种疾病的发生发展有关。异位 DNA 诱导的炎症反应参与了多种病理过程。组织和代谢细胞器的反复损伤会释放出大量损伤相关分子模式（线粒体 DNA、核 DNA 和外源 DNA）。释放到细胞质中的 DNA 片段会被传感器 cGAS 感测到，从而通过桥接蛋白 STING 启动免疫反应。最近的许多研究揭示了 cGAS-STING 信号通路在心血管疾病（CVDs）中的调控作用，如心肌梗死、心力衰竭、动脉粥样硬化和主动脉夹层/动脉瘤。此外，越来越多的证据表明，抑制 cGAS-STING 信号通路可显著抑制心肌肥厚和炎症细胞浸润。因此，本综述旨在确定激活 cGAS-STING 通路的风险因素，以降低风险，同时进一步阐明该通路在心血管领域的生物学功能及其作为治疗靶点的潜力。
{"title":"The cGAS-STING pathway in cardiovascular diseases: from basic research to clinical perspectives.","authors":"Cheng An, Zhen Li, Yao Chen, Shaojun Huang, Fan Yang, Ying Hu, Tao Xu, Chengxin Zhang, Shenglin Ge","doi":"10.1186/s13578-024-01242-4","DOIUrl":"10.1186/s13578-024-01242-4","url":null,"abstract":"<p><p>The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, an important component of the innate immune system, is involved in the development of several diseases. Ectopic DNA-induced inflammatory responses are involved in several pathological processes. Repeated damage to tissues and metabolic organelles releases a large number of damage-associated molecular patterns (mitochondrial DNA, nuclear DNA, and exogenous DNA). The DNA fragments released into the cytoplasm are sensed by the sensor cGAS to initiate immune responses through the bridging protein STING. Many recent studies have revealed a regulatory role of the cGAS-STING signaling pathway in cardiovascular diseases (CVDs) such as myocardial infarction, heart failure, atherosclerosis, and aortic dissection/aneurysm. Furthermore, increasing evidence suggests that inhibiting the cGAS-STING signaling pathway can significantly inhibit myocardial hypertrophy and inflammatory cell infiltration. Therefore, this review is intended to identify risk factors for activating the cGAS-STING pathway to reduce risks and to simultaneously further elucidate the biological function of this pathway in the cardiovascular field, as well as its potential as a therapeutic target.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"58"},"PeriodicalIF":7.5,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11080250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-04DOI: 10.1186/s13578-024-01238-0
Jinju Lee, Mi-Yeon Kim, Hyo Jeong Kim, Woo Sun Choi, Hun Sik Kim
Psoriasis is an inflammatory skin disease characterized by the hyperproliferative epidermal keratinocytes and significant immune cells infiltration, leading to cytokines production such as IL-1β, TNF-α, IL-23, and IL-17. Recent study highlights the critical role of IL-1β in the induction and activation of pathogenic Th17 and IL-17-producing γδ T cells, contributing to psoriasis. However, the mechanism underlying IL-1β dysregulation in psoriasis pathogenesis is unclear. Autophagy regulates IL-1β production and has a pleiotropic effect on inflammatory disorders. Previous studies showed controversial role of autophagy in psoriasis pathogenesis, either pro-inflammatory in autophagy-deficient keratinocyte or anti-inflammatory in pharmacologically autophagy-promoting macrophages. Thus, the direct role of autophagy and its therapeutic potential in psoriasis remains unclear. We used myeloid cell-specific autophagy-related gene 7 (Atg7)-deficient mice and determined the effect of autophagy deficiency in myeloid cells on neutrophilia and disease pathogenesis in an imiquimod-induced psoriasis mouse model. We then assessed the pathogenic mechanism focusing on immune cells producing IL-1β and IL-17 along with gene expression profiles associated with psoriasis in mouse model and public database on patients. Moreover, therapeutic potential of IL-1β blocking in such context was assessed. We found that autophagy deficiency in myeloid cells exacerbated neutrophilic inflammation and disease pathogenesis in mice with psoriasis. This autophagy-dependent effect was associated with a significant increase in IL-1β production from myeloid cells, particularly macrophages, Cxcl2 expression, and IL-17 A producing T cells including γδ T cells. Supporting this, treatment with systemic IL-1 receptor blocking antibody or topical saccharin, a disaccharide suppressing pro-IL-1β expression, led to the alleviation of neutrophilia and psoriatic skin inflammation linked to autophagy deficiency. The pathophysiological relevance of this finding was supported by dysregulation of autophagy-related genes and their correlation with Th17 cytokines in psoriatic skin lesion from patients with psoriasis. Our results suggest that autophagy dysfunction in myeloid cells, especially macrophages, along with IL-1β dysregulation has a causal role in neutrophilic inflammation and psoriasis pathogenesis.
{"title":"Impaired autophagy in myeloid cells aggravates psoriasis-like skin inflammation through the IL-1β/CXCL2/neutrophil axis","authors":"Jinju Lee, Mi-Yeon Kim, Hyo Jeong Kim, Woo Sun Choi, Hun Sik Kim","doi":"10.1186/s13578-024-01238-0","DOIUrl":"https://doi.org/10.1186/s13578-024-01238-0","url":null,"abstract":"Psoriasis is an inflammatory skin disease characterized by the hyperproliferative epidermal keratinocytes and significant immune cells infiltration, leading to cytokines production such as IL-1β, TNF-α, IL-23, and IL-17. Recent study highlights the critical role of IL-1β in the induction and activation of pathogenic Th17 and IL-17-producing γδ T cells, contributing to psoriasis. However, the mechanism underlying IL-1β dysregulation in psoriasis pathogenesis is unclear. Autophagy regulates IL-1β production and has a pleiotropic effect on inflammatory disorders. Previous studies showed controversial role of autophagy in psoriasis pathogenesis, either pro-inflammatory in autophagy-deficient keratinocyte or anti-inflammatory in pharmacologically autophagy-promoting macrophages. Thus, the direct role of autophagy and its therapeutic potential in psoriasis remains unclear. We used myeloid cell-specific autophagy-related gene 7 (Atg7)-deficient mice and determined the effect of autophagy deficiency in myeloid cells on neutrophilia and disease pathogenesis in an imiquimod-induced psoriasis mouse model. We then assessed the pathogenic mechanism focusing on immune cells producing IL-1β and IL-17 along with gene expression profiles associated with psoriasis in mouse model and public database on patients. Moreover, therapeutic potential of IL-1β blocking in such context was assessed. We found that autophagy deficiency in myeloid cells exacerbated neutrophilic inflammation and disease pathogenesis in mice with psoriasis. This autophagy-dependent effect was associated with a significant increase in IL-1β production from myeloid cells, particularly macrophages, Cxcl2 expression, and IL-17 A producing T cells including γδ T cells. Supporting this, treatment with systemic IL-1 receptor blocking antibody or topical saccharin, a disaccharide suppressing pro-IL-1β expression, led to the alleviation of neutrophilia and psoriatic skin inflammation linked to autophagy deficiency. The pathophysiological relevance of this finding was supported by dysregulation of autophagy-related genes and their correlation with Th17 cytokines in psoriatic skin lesion from patients with psoriasis. Our results suggest that autophagy dysfunction in myeloid cells, especially macrophages, along with IL-1β dysregulation has a causal role in neutrophilic inflammation and psoriasis pathogenesis.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"89 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute lung injury (ALI) is strongly associated with hospitalization and mortality in patients with sepsis. Recent evidence suggests that pyroptosis mediated by NLRP3(NOD-, LRR- and pyrin domain-containing 3) inflammasome activation plays a key role in sepsis. However, the mechanism of NLRP3 inflammasome activation in sepsis-induced lung injury remains unclear. in this study, we demonstrated that NLRP3 inflammasome was activated by the down-regulation of heat shock protein family A member 8 (HSPA8) in Lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-treated mouse alveolar epithelial cells (AECs). Geranylgeranylacetone (GGA)-induced HSPA8 overexpression in cecum ligation and puncture (CLP) mice could significantly reduce systemic inflammatory response and mortality, effectively protect lung function, whilst HSPA8 inhibitor VER155008 aggravated this effect. The inhibition of HSPA8 was involved in sepsis induced acute lung injury by promoting pyroptosis of AECs. The down-regulation of HSPA8 activated NLRP3 inflammasome to mediate pyroptosis by promoting the degradation of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). In addition, when stimulated by LPS and ATP, down-regulated SKP2 promoted pyroptosis of AECs by further attenuating ubiquitination of NLRP3. Adeno-associated virus 9-SKP2(AAV9-SKP2) could promote NLRP3 ubiquitination and degradation, alleviate lung injury and inhibit systemic inflammatory response in vivo. in summary, our study shows there is strong statistical evidence that the suppression of HSPA8 mediates alveolar epithelial pyroptosis by promoting the degradation of E3 ubiquitin ligase SKP2 and subsequently attenuating the ubiquitination of NLRP3 to activate the NLRP3 inflammasome, which provides a new perspective and therapeutic target for the treatment of sepsis-induced lung injury.
急性肺损伤（ALI）与脓毒症患者的住院时间和死亡率密切相关。最近的证据表明，由 NLRP3（含 NOD、LRR 和 pyrin 结构域的 3）炎性体激活介导的热变态反应在脓毒症中起着关键作用。在本研究中，我们证明了在脂多糖（LPS）和三磷酸腺苷（ATP）处理的小鼠肺泡上皮细胞（AECs）中，NLRP3 炎性体通过下调热休克蛋白家族 A 成员 8（HSPA8）而被激活。在盲肠结扎和穿刺（CLP）小鼠中，香叶基丙酮（GGA）诱导的HSPA8过表达可显著降低全身炎症反应和死亡率，有效保护肺功能，而HSPA8抑制剂VER155008则会加重这种效应。HSPA8抑制剂通过促进AECs的脓毒症急性肺损伤。HSPA8 的下调激活了 NLRP3 炎症小体，通过促进 E3 泛素连接酶 S 期激酶相关蛋白 2（SKP2）的降解来介导脓毒症。此外，当受到 LPS 和 ATP 的刺激时，下调的 SKP2 会通过进一步减少 NLRP3 的泛素化来促进 AECs 的热解。腺相关病毒9-SKP2（AAV9-SKP2）可促进NLRP3泛素化和降解，减轻肺损伤并抑制体内全身炎症反应。总之，我们的研究表明，有强有力的统计学证据表明，HSPA8的抑制通过促进E3泛素连接酶SKP2的降解，进而减弱NLRP3的泛素化，激活NLRP3炎性体，从而介导肺泡上皮细胞的脓毒症，这为治疗脓毒症引起的肺损伤提供了一个新的视角和治疗靶点。
{"title":"The suppression of HSPA8 attenuates NLRP3 ubiquitination through SKP2 to promote pyroptosis in sepsis-induced lung injury","authors":"Jinlian Liu, Ke Song, Bingqi Lin, Zhenfeng Chen, Yan Liu, Xianshuai Qiu, Qi He, Zirui Zuo, Xiaodan Yao, Xiaoxia Huang, Zhuanhua Liu, Zhifeng Liu, Qiaobing Huang, Xiaohua Guo","doi":"10.1186/s13578-024-01239-z","DOIUrl":"https://doi.org/10.1186/s13578-024-01239-z","url":null,"abstract":"Acute lung injury (ALI) is strongly associated with hospitalization and mortality in patients with sepsis. Recent evidence suggests that pyroptosis mediated by NLRP3(NOD-, LRR- and pyrin domain-containing 3) inflammasome activation plays a key role in sepsis. However, the mechanism of NLRP3 inflammasome activation in sepsis-induced lung injury remains unclear. in this study, we demonstrated that NLRP3 inflammasome was activated by the down-regulation of heat shock protein family A member 8 (HSPA8) in Lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-treated mouse alveolar epithelial cells (AECs). Geranylgeranylacetone (GGA)-induced HSPA8 overexpression in cecum ligation and puncture (CLP) mice could significantly reduce systemic inflammatory response and mortality, effectively protect lung function, whilst HSPA8 inhibitor VER155008 aggravated this effect. The inhibition of HSPA8 was involved in sepsis induced acute lung injury by promoting pyroptosis of AECs. The down-regulation of HSPA8 activated NLRP3 inflammasome to mediate pyroptosis by promoting the degradation of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). In addition, when stimulated by LPS and ATP, down-regulated SKP2 promoted pyroptosis of AECs by further attenuating ubiquitination of NLRP3. Adeno-associated virus 9-SKP2(AAV9-SKP2) could promote NLRP3 ubiquitination and degradation, alleviate lung injury and inhibit systemic inflammatory response in vivo. in summary, our study shows there is strong statistical evidence that the suppression of HSPA8 mediates alveolar epithelial pyroptosis by promoting the degradation of E3 ubiquitin ligase SKP2 and subsequently attenuating the ubiquitination of NLRP3 to activate the NLRP3 inflammasome, which provides a new perspective and therapeutic target for the treatment of sepsis-induced lung injury.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"88 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF.
{"title":"Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation","authors":"Zi-Ying Lei, Zhi-Hui Li, Deng-Na Lin, Jing Cao, Jun-Feng Chen, Shi-Bo Meng, Jia-Lei Wang, Jing Liu, Jing Zhang, Bing-Liang Lin","doi":"10.1186/s13578-024-01234-4","DOIUrl":"https://doi.org/10.1186/s13578-024-01234-4","url":null,"abstract":"Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF. ","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"29 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140805025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients. We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes. Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.
{"title":"Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis","authors":"Chong Xu, Yilan Mei, Ruihan Yang, Qiudan Luo, Jienian Zhang, Xiaolin Kou, Jianfeng Hu, Yujie Wang, Yue Li, Rong Chen, Zhengping Zhang, Yuyuan Yao, Jian Sima","doi":"10.1186/s13578-024-01230-8","DOIUrl":"https://doi.org/10.1186/s13578-024-01230-8","url":null,"abstract":"Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients. We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes. Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"27 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140805140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Data on the course of viral infections revealed severe inflammation as a consequence of antiviral immune response. Despite extensive research, there are insufficient data on the role of innate immune cells in promoting inflammation mediated by immune complexes (IC) of viral antigens and their specific antibodies. Recently, we demonstrated that antigens of human polyomaviruses (PyVs) induce an inflammatory response in macrophages. Here, we investigated macrophage activation by IC. We used primary murine macrophages as a cell model, virus-like particles (VLPs) of PyV capsid protein as antigens, and a collection of murine monoclonal antibodies (mAbs) of IgG1, IgG2a, IgG2b subclasses. The inflammatory response was investigated by analysing inflammatory chemokines and activation of NLRP3 inflammasome. We observed a diverse pattern of chemokine secretion in macrophages treated with different IC compared to VLPs alone. To link IC properties with cell activation status, we characterised the IC by advanced optical and acoustic techniques. Ellipsometry provided precise real-time kinetics of mAb-antigen interactions, while quartz crystal microbalance measurements showed changes in conformation and viscoelastic properties during IC formation. These results revealed differences in mAb-antigen interaction and mAb binding parameters of the investigated IC. We found that IC-mediated cell activation depends more on IC characteristics, including mAb affinity, than on mAb affinity for the activating Fc receptor. IC formed by the highest affinity mAb showed a significant enhancement of inflammasome activation. This may explain the hyperinflammation related to viral infection and vaccination. Our findings demonstrate that IC promote the viral antigen-induced inflammatory response depending on antibody properties.
有关病毒感染过程的数据显示，严重的炎症是抗病毒免疫反应的结果。尽管进行了大量研究，但关于先天性免疫细胞在由病毒抗原及其特异性抗体组成的免疫复合物（IC）介导的炎症中的作用，目前还没有足够的数据。最近，我们证实人类多瘤病毒（PyVs）的抗原会诱导巨噬细胞产生炎症反应。在此，我们研究了 IC 对巨噬细胞的激活作用。我们使用原代小鼠巨噬细胞作为细胞模型，PyV 荚膜蛋白的病毒样颗粒（VLPs）作为抗原，以及一系列小鼠 IgG1、IgG2a、IgG2b 亚类单克隆抗体（mAbs）。通过分析炎症趋化因子和 NLRP3 炎症小体的激活情况，研究了炎症反应。与单独使用 VLPs 相比，我们观察到在使用不同 IC 处理的巨噬细胞中，趋化因子的分泌模式多种多样。为了将集成电路的特性与细胞活化状态联系起来，我们采用先进的光学和声学技术对集成电路进行了表征。椭偏仪提供了 mAb 与抗原相互作用的精确实时动力学，而石英晶体微天平测量则显示了 IC 形成过程中构象和粘弹性的变化。这些结果揭示了所研究的集成电路在 mAb 抗原相互作用和 mAb 结合参数方面的差异。我们发现，IC 介导的细胞活化更多地取决于 IC 的特性，包括 mAb 亲和力，而不是 mAb 与活化 Fc 受体的亲和力。亲和力最高的 mAb 所形成的 IC 能显著增强炎症小体的激活。这可能解释了与病毒感染和疫苗接种有关的高炎症反应。我们的研究结果表明，IC 促进病毒抗原诱导的炎症反应取决于抗体的特性。
{"title":"Structural properties of immune complexes formed by viral antigens and specific antibodies shape the inflammatory response of macrophages","authors":"Asta Lučiūnaitė, Kristina Mašalaitė, Ieva Plikusiene, Vincentas Maciulis, Silvija Juciute, Milda Norkienė, Aurelija Žvirblienė","doi":"10.1186/s13578-024-01237-1","DOIUrl":"https://doi.org/10.1186/s13578-024-01237-1","url":null,"abstract":"Data on the course of viral infections revealed severe inflammation as a consequence of antiviral immune response. Despite extensive research, there are insufficient data on the role of innate immune cells in promoting inflammation mediated by immune complexes (IC) of viral antigens and their specific antibodies. Recently, we demonstrated that antigens of human polyomaviruses (PyVs) induce an inflammatory response in macrophages. Here, we investigated macrophage activation by IC. We used primary murine macrophages as a cell model, virus-like particles (VLPs) of PyV capsid protein as antigens, and a collection of murine monoclonal antibodies (mAbs) of IgG1, IgG2a, IgG2b subclasses. The inflammatory response was investigated by analysing inflammatory chemokines and activation of NLRP3 inflammasome. We observed a diverse pattern of chemokine secretion in macrophages treated with different IC compared to VLPs alone. To link IC properties with cell activation status, we characterised the IC by advanced optical and acoustic techniques. Ellipsometry provided precise real-time kinetics of mAb-antigen interactions, while quartz crystal microbalance measurements showed changes in conformation and viscoelastic properties during IC formation. These results revealed differences in mAb-antigen interaction and mAb binding parameters of the investigated IC. We found that IC-mediated cell activation depends more on IC characteristics, including mAb affinity, than on mAb affinity for the activating Fc receptor. IC formed by the highest affinity mAb showed a significant enhancement of inflammasome activation. This may explain the hyperinflammation related to viral infection and vaccination. Our findings demonstrate that IC promote the viral antigen-induced inflammatory response depending on antibody properties.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"19 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140805340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.1186/s13578-024-01233-5
Zhao Cai
The evolution of demyelination in individual internodes remains unclear although it has been noticed the paranodal demyelination precedes internodal demyelination in neuropathies with diverse aetiologies. For therapeutic purpose, it is fundamental to know whether the demyelinating procedure in affected internodes can be interrupted. This study aimed to delineate the development of demyelination in individual internodes in avian riboflavin deficient neuropathy. Newborn broiler meat chickens were maintained either on a routine diet containing 5.0 mg/kg riboflavin, a riboflavin deficient diet containing 1.8 mg/kg riboflavin, or initially a riboflavin deficient diet for 11 days and then routine diet plus riboflavin repletion from day 12. Evolution of demyelination in individual internodes was analyzed by teased nerve fibre studies from day 11 to 21. In riboflavin deficient chickens, demyelination was the predominant feature: it was mainly confined to the paranodal region at day 11; extended into internodal region, but less than half of the internodal length in most affected internodes at day 16; involved more than half or whole internode at day 21. In the internode undergoing demyelination, myelin degeneration of varying degrees was noticed in the cytoplasm of the Schwann cell wrapping the internode. Two days after riboflavin repletion, co-existence of remyelination and active demyelination within individual internodes was noticed. Remyelination together with preserved short original internodes was the characteristic feature 4 and 9 days after riboflavin repletion. Riboflavin repletion interrupts the progression from paranodal to internodal demyelination in riboflavin deficient chickens and promotes remyelination before complete internodal demyelination.
{"title":"Interruptible demyelination in avian riboflavin deficient neuropathy","authors":"Zhao Cai","doi":"10.1186/s13578-024-01233-5","DOIUrl":"https://doi.org/10.1186/s13578-024-01233-5","url":null,"abstract":"The evolution of demyelination in individual internodes remains unclear although it has been noticed the paranodal demyelination precedes internodal demyelination in neuropathies with diverse aetiologies. For therapeutic purpose, it is fundamental to know whether the demyelinating procedure in affected internodes can be interrupted. This study aimed to delineate the development of demyelination in individual internodes in avian riboflavin deficient neuropathy. Newborn broiler meat chickens were maintained either on a routine diet containing 5.0 mg/kg riboflavin, a riboflavin deficient diet containing 1.8 mg/kg riboflavin, or initially a riboflavin deficient diet for 11 days and then routine diet plus riboflavin repletion from day 12. Evolution of demyelination in individual internodes was analyzed by teased nerve fibre studies from day 11 to 21. In riboflavin deficient chickens, demyelination was the predominant feature: it was mainly confined to the paranodal region at day 11; extended into internodal region, but less than half of the internodal length in most affected internodes at day 16; involved more than half or whole internode at day 21. In the internode undergoing demyelination, myelin degeneration of varying degrees was noticed in the cytoplasm of the Schwann cell wrapping the internode. Two days after riboflavin repletion, co-existence of remyelination and active demyelination within individual internodes was noticed. Remyelination together with preserved short original internodes was the characteristic feature 4 and 9 days after riboflavin repletion. Riboflavin repletion interrupts the progression from paranodal to internodal demyelination in riboflavin deficient chickens and promotes remyelination before complete internodal demyelination.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"279 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140805138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pain is a common symptom of many diseases with a high incidence rate. Clinically, drug treatment, as the main method to relieve pain at present, is often accompanied by different degrees of adverse reactions. Therefore, it is urgent to gain a profound understanding of the pain mechanisms in order to develop advantageous analgesic targets. The PD-L1/PD-1 pathway, an important inhibitory molecule in the immune system, has taken part in regulating neuroinflammation and immune response. Accumulating evidence indicates that the PD-L1/PD-1 pathway is aberrantly activated in various pain models. And blocking PD-L1/PD-1 pathway will aggravate pain behaviors. This review aims to summarize the emerging evidence on the role of the PD-L1/PD-1 pathway in alleviating pain and provide an overview of the mechanisms involved in pain resolution, including the regulation of macrophages, microglia, T cells, as well as nociceptor neurons. However, its underlying mechanism still needs to be further elucidated in the future. In conclusion, despite more deep researches are needed, these pioneering studies indicate that PD-L1/PD-1 may be a potential neuroimmune target for pain relief.
{"title":"PD-L1/PD-1 pathway: a potential neuroimmune target for pain relief","authors":"Daling Deng, Tianhao Zhang, Lulin Ma, Wenjing Zhao, Shiqian Huang, Kaixing Wang, Shaofang Shu, Xiangdong Chen","doi":"10.1186/s13578-024-01227-3","DOIUrl":"https://doi.org/10.1186/s13578-024-01227-3","url":null,"abstract":"Pain is a common symptom of many diseases with a high incidence rate. Clinically, drug treatment, as the main method to relieve pain at present, is often accompanied by different degrees of adverse reactions. Therefore, it is urgent to gain a profound understanding of the pain mechanisms in order to develop advantageous analgesic targets. The PD-L1/PD-1 pathway, an important inhibitory molecule in the immune system, has taken part in regulating neuroinflammation and immune response. Accumulating evidence indicates that the PD-L1/PD-1 pathway is aberrantly activated in various pain models. And blocking PD-L1/PD-1 pathway will aggravate pain behaviors. This review aims to summarize the emerging evidence on the role of the PD-L1/PD-1 pathway in alleviating pain and provide an overview of the mechanisms involved in pain resolution, including the regulation of macrophages, microglia, T cells, as well as nociceptor neurons. However, its underlying mechanism still needs to be further elucidated in the future. In conclusion, despite more deep researches are needed, these pioneering studies indicate that PD-L1/PD-1 may be a potential neuroimmune target for pain relief.","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"62 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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