{"title":"First trimester human umbilical cord perivascular cells (HUCPVC) modulate the kynurenine pathway and glutamate neurotransmission in an LPS-induced mouse model of neuroinflammation.","authors":"Fyyaz Siddiqui, Denis Gallagher, Hannah Shuster-Hyman, Lianet Lopez, Andrée Gauthier-Fisher, Clifford L Librach","doi":"10.1186/s12950-023-00340-3","DOIUrl":"https://doi.org/10.1186/s12950-023-00340-3","url":null,"abstract":"<p><strong>Background: </strong>The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. The therapeutic potential of mesenchymal stromal cells (MSC), owing to their well documented phagocytosis-driven mechanism of immunomodulation and neuroprotection, has been tested in many neurological disorders. However, their potential to influence KP and the glutamatergic system has not yet been investigated. Hence, this study sought to investigate the effect of HUCPVC, a rich and potent source of MSC, on Lipopolysaccharide (LPS)-activated KP metabolites, KP enzymes, and key components of glutamate neurotransmission.</p><p><strong>Methods: </strong>The immunomodulatory effect of peripherally administered HUCPVC on the expression profile of kynurenine pathway metabolites and enzymes was assessed in the plasma and brain of mice treated with LPS using LCMS and QPCR. An assessment of the glutamatergic system, including selected receptors, transporters and related proteins was also conducted by QPCR, immunohistochemistry and Western blot.</p><p><strong>Results: </strong>HUCPVC were found to modulate LPS-induced activation of KP enzymes and metabolites in the brain associated with neurotoxicity. Moreover, the reduced expression of the glutamatergic components due to LPS was also found to be significantly improved by HUCPVC.</p><p><strong>Conclusions: </strong>The immunomodulatory properties of HUCPVC appear to confer neuroprotection, at least in part, through their ability to modulate the KP in the brain. This KP modulation enhances neuroprotective regulators and downregulates neurotoxic consequences, including glutamate neurotoxicity, which is associated with neuroinflammation and depressive behavior.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"15"},"PeriodicalIF":5.1,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9773397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dioscin alleviates the progression of osteoarthritis: an in vitro and in vivo study.","authors":"Qing Ding, Ruizhuo Zhang, Gaohong Sheng, Tianqi Wang, Shaoze Jing, Tian Ma, Shanxi Wang, Hongqi Zhao, Hua Wu, Wenkai Li","doi":"10.1186/s12950-023-00339-w","DOIUrl":"https://doi.org/10.1186/s12950-023-00339-w","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a common joint disease and is the main cause of physical disability in the elderly. Currently, there is no adequate therapeutic strategy to reverse the progression of OA. Many natural plant extracts have received attention in the treatment of OA due to their potential anti-inflammatory properties, and reduced incidence of adverse events. Dioscin (Dio), a natural steroid saponin, has been demonstrated to inhibit the release of inflammatory cytokines in mouse and rat models of various diseases, and has a protective effect in chronic inflammatory diseases. However, whether Dio alleviates OA progression remains to be explored. In this research, our purposes were to investigate the therapeutic potential of Dio in OA. The results demonstrated that Dio exerted anti-inflammatory effects by repressing NO, PGE<sub>2</sub>, iNOS and COX-2. Moreover, the application of Dio could repress IL-1β-induced overexpression of matrix metalloproteinases (MMPs, including MMP1, MMP3, and MMP13) and ADAMTS-5, and improve the synthesis of collagen II and aggrecan, which contribute to the maintenance of chondrocyte matrix homeostasis. The underlying mechanism involved the inhibition of the MAPK and NF-κB signaling pathways by Dio. Furthermore, the treatment of Dio significantly improved the pain behaviors of rat OA models. The in vivo study revealed that Dio could ameliorate cartilage erosion and degradation. These results collectively indicate that Dio can be used as a promising and effective agent for the therapy of OA.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"14"},"PeriodicalIF":5.1,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9311773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yeomyeong Kim, Cho-Rong Bae, Dongyeop Kim, Hyejeong Kim, Sunghye Lee, Haiying Zhang, Minyoung Noh, Young-Myeong Kim, Naoki Mochizuki, Young-Guen Kwon
{"title":"Efficacy of CU06-1004 via regulation of inflammation and endothelial permeability in LPS-induced acute lung injury.","authors":"Yeomyeong Kim, Cho-Rong Bae, Dongyeop Kim, Hyejeong Kim, Sunghye Lee, Haiying Zhang, Minyoung Noh, Young-Myeong Kim, Naoki Mochizuki, Young-Guen Kwon","doi":"10.1186/s12950-023-00338-x","DOIUrl":"https://doi.org/10.1186/s12950-023-00338-x","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) is a life-threatening condition that fundamentally results from inflammation and edema in the lung. There are no effective treatments available for clinical use. Previously, we found that as a leakage blocker CU06-1004 prevents endothelial barrier disruption and enhances endothelial cell survival under inflammatory conditions. In this study, we aimed to elucidate the effect of CU06-1004 in terms of prevention of inflammation and endothelial dysfunction in an ALI mouse model.</p><p><strong>Methods: </strong>An ALI model was established that included intraperitoneal administration of LPS. Following LPS administration, survival rates and lung wet/dry ratios were assessed. Histological analysis was performed using hematoxylin and eosin staining. Scanning electron microscopy was used to examine alveolar and capillary morphology. Cytokines such as IL-1β, IL-6, and TNF-α were analyzed using an ELISA assay of bronchoalveolar lavage fluid (BALF) and serum. Neutrophil infiltration was observed in BALF using Wright-Giemsa staining, and myeloperoxidase (MPO) activity was assessed. Pulmonary vascular leakage was confirmed using Evans-blue dye, and the expression of junctional proteins was evaluated using immunofluorescent staining. Expression of adhesion molecules was observed using immunofluorescence staining. NF-κB activation was determined using immunohistochemistry and western blot analysis.</p><p><strong>Results: </strong>Survival rates and pulmonary edema were ameliorated with CU06-1004 treatment. Administration of CU06-1004 normalized histopathological changes induced by LPS, and alveolar-capillary wall thickening was reduced. Compared with the LPS-challenged group, after CU06-1004 treatment, the infiltration of immune cells was decreased in the BALF, and MPO activity in lung tissue was reduced. Similarly, in the CU06-1004 treatment group, pro-inflammatory cytokines were significantly inhibited in both BALF and serum. Evans-blue leakage was reduced, and the expression of junctional proteins was recovered in the CU06-1004 group. Adhesion molecules were downregulated and NF-κB activation was inhibited after CU06-1004 treatment.</p><p><strong>Conclusions: </strong>These results suggested that CU06-1004 had a therapeutic effect against LPS-induced ALI via alleviation of the inflammatory response and protection of vascular integrity.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"13"},"PeriodicalIF":5.1,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10078077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9275907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matti Hoch, Suchi Smita, Konstantin Cesnulevicius, Myron Schultz, David Lescheid, Olaf Wolkenhauer, Shailendra Gupta
{"title":"Network analyses reveal new insights into the effect of multicomponent Tr14 compared to single-component diclofenac in an acute inflammation model.","authors":"Matti Hoch, Suchi Smita, Konstantin Cesnulevicius, Myron Schultz, David Lescheid, Olaf Wolkenhauer, Shailendra Gupta","doi":"10.1186/s12950-023-00335-0","DOIUrl":"https://doi.org/10.1186/s12950-023-00335-0","url":null,"abstract":"<p><strong>Background: </strong>Modifying the acute inflammatory response has wide clinical benefits. Current options include non-steroidal anti-inflammatory drugs (NSAIDs) and therapies that may resolve inflammation. Acute inflammation involves multiple cell types and various processes. We, therefore, investigated whether an immunomodulatory drug that acts simultaneously at multiple sites shows greater potential to resolve acute inflammation more effectively and with fewer side effects than a common anti-inflammatory drug developed as a small molecule for a single target. In this work, we used time-series gene expression profiles from a wound healing mouse model to compare the effects of Traumeel (Tr14), a multicomponent natural product, to diclofenac, a single component NSAID on inflammation resolution.</p><p><strong>Results: </strong>We advance previous studies by mapping the data onto the \"Atlas of Inflammation Resolution\", followed by in silico simulations and network analysis. We found that Tr14 acts primarily on the late phase of acute inflammation (during resolution) compared to diclofenac, which suppresses acute inflammation immediately after injury.</p><p><strong>Conclusions: </strong>Our results provide new insights how network pharmacology of multicomponent drugs may support inflammation resolution in inflammatory conditions.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"12"},"PeriodicalIF":5.1,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10044762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9202468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gaetano Scaramuzzo, Francesco Nucera, Alessio Asmundo, Roberto Messina, Matilde Mari, Federica Montanaro, Matt D Johansen, Francesco Monaco, Guido Fadda, Giovanni Tuccari, Nicole G Hansbro, Philip M Hansbro, Trevor T Hansel, Ian M Adcock, Antonio David, Paul Kirkham, Gaetano Caramori, Carlo Alberto Volta, Savino Spadaro
{"title":"Cellular and molecular features of COVID-19 associated ARDS: therapeutic relevance.","authors":"Gaetano Scaramuzzo, Francesco Nucera, Alessio Asmundo, Roberto Messina, Matilde Mari, Federica Montanaro, Matt D Johansen, Francesco Monaco, Guido Fadda, Giovanni Tuccari, Nicole G Hansbro, Philip M Hansbro, Trevor T Hansel, Ian M Adcock, Antonio David, Paul Kirkham, Gaetano Caramori, Carlo Alberto Volta, Savino Spadaro","doi":"10.1186/s12950-023-00333-2","DOIUrl":"10.1186/s12950-023-00333-2","url":null,"abstract":"<p><p>The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support.The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"11"},"PeriodicalIF":4.4,"publicationDate":"2023-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9161550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Petra Kosutova, Pavol Mikolka, Daniela Mokra, Andrea Calkovska
{"title":"Anti-inflammatory activity of non-selective PDE inhibitor aminophylline on the lung tissue and respiratory parameters in animal model of ARDS.","authors":"Petra Kosutova, Pavol Mikolka, Daniela Mokra, Andrea Calkovska","doi":"10.1186/s12950-023-00337-y","DOIUrl":"https://doi.org/10.1186/s12950-023-00337-y","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) is a common complication of critical illness characterized by lung inflammation, epithelial and endothelial dysfunction, alveolar-capillary leakage, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory effects of non-selective phosphodiesterase (PDE) inhibitor aminophylline. New Zealand white rabbits were randomly divided into 3 groups: animals with respiratory failure defined as PaO<sub>2</sub>/FiO<sub>2</sub> ratio (P/F) below < 26.7 kPa, and induced by saline lung lavage (ARDS), animals with ARDS treated with intravenous aminophylline (1 mg/kg; ARDS/AMINO), and healthy ventilated controls (Control). All animals were oxygen ventilated for an additional 4 h and respiratory parameters were recorded regularly. Post mortem, the lung tissue was evaluated for oedema formation, markers of inflammation (tumor necrosis factor, TNFα, interleukin (IL)-1β, -6, -8, -10, -13, -18), markers of epithelial damage (receptor for advanced glycation end products, RAGE) and endothelial injury (sphingosine 1-phosphate, S1P), oxidative damage (thiobarbituric acid reactive substances, TBARS, 3-nitrotyrosine, 3NT, total antioxidant capacity, TAC). Aminophylline therapy decreased the levels of pro-inflammatory cytokines, markers of epithelial and endothelial injury, oxidative modifications in lung tissue, reduced lung oedema, and improved lung function parameters compared to untreated ARDS animals. In conclusion, non-selective PDE inhibitor aminophylline showed a significant anti-inflammatory activity suggesting a potential of this drug to be a valuable component of ARDS therapy.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"10"},"PeriodicalIF":5.1,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10018984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9127335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinkun Cheng, Torsten Lowin, Nadine Honke, Georg Pongratz
{"title":"Components of the sympathetic nervous system as targets to modulate inflammation - rheumatoid arthritis synovial fibroblasts as neuron-like cells?","authors":"Xinkun Cheng, Torsten Lowin, Nadine Honke, Georg Pongratz","doi":"10.1186/s12950-023-00336-z","DOIUrl":"https://doi.org/10.1186/s12950-023-00336-z","url":null,"abstract":"<p><strong>Background: </strong>Catecholamines are major neurotransmitters of the sympathetic nervous system (SNS) and they are of pivotal importance in regulating numerous physiological and pathological processes. Rheumatoid arthritis (RA) is influenced by the activity of the SNS and its neurotransmitters norepinephrine (NE) and dopamine (DA) and early sympathectomy alleviates experimental arthritis in mice. In contrast, late sympathectomy aggravates RA, since this procedure eliminates anti-inflammatory, tyrosine hydroxylase (TH) positive cells that appear in the course of RA. While it has been shown that B cells can take up, degrade and synthesize catecholamines it is still unclear whether this also applies to synovial fibroblasts, a mesenchymal cell that is actively engaged in propagating inflammation and cartilage destruction in RA. Therefore, this study aims to present a detailed description of the catecholamine pathway and its influence on human RA synovial fibroblasts (RASFs).</p><p><strong>Results: </strong>RASFs express all catecholamine-related targets including the synthesizing enzymes TH, DOPA decarboxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase. Furthermore, vesicular monoamine transporters 1/2 (VMAT1/2), dopamine transporter (DAT) and norepinephrine transporter (NET) were detected. RASFs are also able to degrade catecholamines as they express monoaminoxidase A and B (MAO-A/MAO-B) and catechol-O-methyltransferase (COMT). TNF upregulated VMAT2, MAO-B and NET levels in RASFs. DA, NE and epinephrine (EPI) were produced by RASFs and extracellular levels were augmented by either MAO, COMT, VMAT or DAT/NET inhibition but also by tumor necrosis factor (TNF) stimulation. While exogenous DA decreased interleukin-6 (IL-6) production and cell viability at the highest concentration (100 μM), NE above 1 μM increased IL-6 levels with a concomitant decrease in cell viability. MAO-A and MAO-B inhibition had differential effects on unstimulated and TNF treated RASFs. The MAO-A inhibitor clorgyline fostered IL-6 production in unstimulated but not TNF stimulated RASFs (10 nM-1 μM) while reducing IL-6 at 100 μM with a dose-dependent decrease in cell viability in both groups. The MAO-B inhibitor lazabemide hydrochloride did only modestly decrease cell viability at 100 μM while enhancing IL-6 production in unstimulated RASFs and decreasing IL-6 in TNF stimulated cells.</p><p><strong>Conclusions: </strong>RASFs possess a complete and functional catecholamine machinery whose function is altered under inflammatory conditions. Results from this study shed further light on the involvement of sympathetic neurotransmitters in RA pathology and might open therapeutic avenues to counteract inflammation with the MAO enzymes being key candidates.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"9"},"PeriodicalIF":5.1,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9179033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-inflammatory therapy of atherosclerosis: focusing on IKKβ.","authors":"Jiali Gan, Lin Guo, Xiaolu Zhang, Qun Yu, Qiuyue Yang, Yilin Zhang, Wenyun Zeng, Xijuan Jiang, Maojuan Guo","doi":"10.1186/s12950-023-00330-5","DOIUrl":"https://doi.org/10.1186/s12950-023-00330-5","url":null,"abstract":"<p><p>Chronic low-grade inflammation has been identified as a major contributor in the development of atherosclerosis. Nuclear Factor-κappa B (NF-κB) is a critical transcription factors family of the inflammatory pathway. As a major catalytic subunit of the IKK complex, IκB kinase β (IKKβ) drives canonical activation of NF-κB and is implicated in the link between inflammation and atherosclerosis, making it a promising therapeutic target. Various natural product derivatives, extracts, and synthetic, show anti-atherogenic potential by inhibiting IKKβ-mediated inflammation. This review focuses on the latest knowledge and current research landscape surrounding anti-atherosclerotic drugs that inhibit IKKβ. There will be more opportunities to fully understand the complex functions of IKKβ in atherogenesis and develop new effective therapies in the future.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"8"},"PeriodicalIF":5.1,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9951513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10791353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sofia Malm Tillgren, Juan José Nieto-Fontarigo, Samuel Cerps, Sangeetha Ramu, Mandy Menzel, Irma Mahmutovic Persson, Anja Meissner, Hamid Akbarshahi, Lena Uller
{"title":"C57Bl/6N mice have an attenuated lung inflammatory response to dsRNA compared to C57Bl/6J and BALB/c mice.","authors":"Sofia Malm Tillgren, Juan José Nieto-Fontarigo, Samuel Cerps, Sangeetha Ramu, Mandy Menzel, Irma Mahmutovic Persson, Anja Meissner, Hamid Akbarshahi, Lena Uller","doi":"10.1186/s12950-023-00331-4","DOIUrl":"https://doi.org/10.1186/s12950-023-00331-4","url":null,"abstract":"<p><strong>Background: </strong>Lower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, synthetic dsRNA can be used as a surrogate for ssRNA virus replication. However, studies investigating how genetic background of mice impacts the murine lung inflammatory response to dsRNA is lacking. Hence, we have compared lung immunological responses of BALB/c, C57Bl/6N and C57Bl/6J mice to synthetic dsRNA.</p><p><strong>Methods: </strong>dsRNA was administered intranasally to BALB/c, C57Bl/6N and C57Bl/6J mice once/day for three consecutive days. Lactate dehydrogenase (LDH) activity, inflammatory cells, and total protein concentration were analyzed in bronchoalveolar lavage fluid (BALF). Pattern recognition receptors levels (TLR3, MDA5 and RIG-I) were measured in lung homogenates using RT-qPCR and western blot. Gene expression of IFN-β, TNF-α, IL-1β and CXCL1 was assessed in lung homogenates by RT-qPCR. ELISA was used to analyze protein concentrations of CXCL1 and IL-1β in BALF and lung homogenates.</p><p><strong>Results: </strong>BALB/c and C57Bl/6J mice showed infiltration of neutrophils to the lung, and an increase in total protein concentration and LDH activity in response to dsRNA administration. Only modest increases in these parameters were observed for C57Bl/6N mice. Similarly, dsRNA administration evoked an upregulation of MDA5 and RIG-I gene and protein expression in BALB/c and C57Bl/6J, but not C57Bl/6N, mice. Further, dsRNA provoked an increase in gene expression of TNF-α in BALB/c and C57Bl/6J mice, IL-1β only in C57Bl/6N mice and CXCL1 exclusively in BALB/c mice. BALF levels of CXCL1 and IL-1β were increased in BALB/c and C57Bl/6J mice in response to dsRNA, whereas the response of C57Bl/6N was blunt. Overall, inter-strain comparisons of the lung reactivity to dsRNA revealed that BALB/c, followed by C57Bl/6J, had the most pronounced respiratory inflammatory responses, while the responses of C57Bl/6N mice were attenuated.</p><p><strong>Conclusions: </strong>We report clear differences of the lung innate inflammatory response to dsRNA between BALB/c, C57Bl/6J and C57Bl/6N mice. Of particular note, the highlighted differences in the inflammatory response of C57Bl/6J and C57Bl/6N substrains underscore the value of strain selection in mouse models of respiratory viral infections.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"6"},"PeriodicalIF":5.1,"publicationDate":"2023-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10759204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xue Cao, Yanhong Li, Yubin Luo, Tianshu Chu, Hang Yang, Ji Wen, Yi Liu, Yi Zhao, Martin Herrmann
{"title":"Transient receptor potential melastatin 2 regulates neutrophil extracellular traps formation and delays resolution of neutrophil-driven sterile inflammation.","authors":"Xue Cao, Yanhong Li, Yubin Luo, Tianshu Chu, Hang Yang, Ji Wen, Yi Liu, Yi Zhao, Martin Herrmann","doi":"10.1186/s12950-023-00334-1","DOIUrl":"https://doi.org/10.1186/s12950-023-00334-1","url":null,"abstract":"<p><p>The formation of neutrophil extracellular traps (NETs) is a process releasing into the extracellular space networks of chromatin fibers decorated with granular proteins. It is implicated in infection-related as well as sterile inflammation. Monosodium urate (MSU) crystals serve as damage-associated molecular pattern (DAMP) in various conditions of disease. Formation of NETs or aggregated NETs (aggNETs) orchestrates initiation and resolution of MSU crystals-triggered inflammation, respectively. Elevated intracellular calcium levels and the generation of reactive oxygen species (ROS) are crucial for the formation of MSU crystal-induced NETs. However, the exact signaling pathways involved are still elusive. Herein, we demonstrate that the ROS-sensing, non-selective calcium-permeable channel transient receptor potential cation channel subfamily M member 2 (TRPM2) is required for a full-blown MSU crystal-induced NET formation. Primary neutrophils from TRPM2<sup>-/-</sup> mice showed reduced calcium influx and ROS production and, consequently a reduced formation of MSU crystal-induced NETs and aggNETs. Furthermore, in TRPM2<sup>-/-</sup> mice the infiltration of inflammatory cells into infected tissues and their production of inflammatory mediators was suppressed. Taken together these results describe an inflammatory role of TRPM2 for neutrophil-driven inflammation and identify TRPM2 as potential target for therapeutic intervention.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"20 1","pages":"7"},"PeriodicalIF":5.1,"publicationDate":"2023-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9313014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}