Podcasts about chemokines

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.503668v1?rss=1 Authors: Licht-Murava, A., Meadows, S. M., Palaguachi, F., Song, S. C., Bram, Y., Zhou, C., Jackvony, S., Schwartz, R. E., Froemke, R. C., Orr, A. L., Orr, A. G. Abstract: TDP-43 pathology is prevalent in dementia but the cell type-specific effects of TDP-43 are not clear and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Long Story Short with Dr. Been Episode 11: Chronic Inflammation (Part 3) - Immune Regulation Mechanisms Continuing with the chronic inflammation series, we will now do a deeper dive in order to understand the regulatory mechanisms of the immune system. In this episode of Long Story Short, we will demonstrate a few examples including persistence of the antigen, negative feedback mechanisms for the innate arm, roles of IL-10, IFN-gamma, and IL-12, antibody feedback and more. In the week's episode we will discuss the role of T Regulatory (TReg) cells. DrBeen: Medical Education Online https://www.drbeen.com/ Home - FLCCC | Front Line COVID-19 Critical Care Alliance https://covid19criticalcare.com/ References: Chronic Inflammation - StatPearls - NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK493173/ Inflammation - Wikipedia https://en.wikipedia.org/wiki/Inflammation Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain - PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753746/ Frontiers | Toll-Like Receptors, Associated Biological Roles, and Signaling Networks in Non-Mammals | Immunology https://www.frontiersin.org/articles/10.3389/fimmu.2018.01523/full Donate to the Front Line Covid-19 Critical Care Alliance, Inc. 
To educate medical professionals and the public in safe and effective ways to prevent and treat COVID-19. Click here to make a donation: https://frontlinecovid-19criticalcarealliance.salsalabs.org/donate/index.html Buy FLCCC gear: https://supportflccc.store/ Subscribe to our mailing list on our website: http://flccc.net/signup Disclaimer: This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only. Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional.

From a doctorate at the SALK Institute overlooking La Jolla Cove, to an MBA from INSEAD, the world-leading business school located near Paris, NOXXON CEO Aram Mangasarian knows his way around different environments. Now he's focused on tackling the tumor micro-environment (TME) and targeting the chemokines that drive tumor immunosuppression. Lead asset, NOX-A12, has generated exciting early results in some of the most challenging tumor types: pancreatic cancer and glioblastoma.

Getting physically injured is no fun—it can often take long periods of time to recover. What if we could accelerate the wound healing process? Here, Kellen dissects an original article, titled “The commensal skin microbiota triggers type I IFN-dependent innate repair responses in injured skin”, that reveals mechanisms underlying skin injury and identifies novel therapeutic approaches to speed up healing. The report was written by Jeremy Di Domizio et al. and was published in Nature Immunology in July of 2020. Paper: https://www.nature.com/articles/s41590-020-0721-6 Commentary: https://www.nature.com/articles/s41590-020-0755-9?proof=t Please take a few minutes to write us a review on iTunes -- it will help us spread science! And please send any questions and comments to inflammatory.content.w.kc@gmail.com or interact with Kellen on Twitter @KellenCavagnero

Dr Jack Cush reviews the news and Journal articles from this past week on RheumNow.com Inf on PsA, CV Risk, Chemokines, relapsing polychondritis, Higher COVID rates in young adults, higher reimbursements for Rheumatologists

Commentary by Dr. Valentin Fuster

Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

Dr. Mario Sznol, Yale School of Medicine, provides a detailed description of the mechanism of action of immunotherapy agents and discusses early data on the use of combination therapies.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler The TWiV team reviews identification of immune biomarkers in CFS/ME patients, and how a cell nuclease controls the innate immune response to vaccinia virus infection. Links for this episode Immune signatures in ME/CFS (Science Adv) 11:15 Systemic exertion intolerance disease (Lancet) 19:50 Cell nuclease controls anti-viral responses (Cell Host Micr) 25:10 Poxvirus decapping enzymes prevent innate responses (Cell Host Micr) 1:15:40 Caps off to poxviruses (Cell Host Micr) Drummer Mohr (YouTube) 1:24:05 Bornavirus in squirrel breeders (ProMedMail) 1:28:45 Principles of Microbial Diversity 5:30 Journal of Microbiology & Biology Education 1:24:25 Cross-stitch by Anne Marie 1:34:40 Letters read on TWiV 329 1:25:00 Timestamps by Jennifer. Thank you! Weekly Science Picks 1:35:10 Alan - NASA Solar Dynamics Observatory videoRich - Mutagenic chain reaction (Video: Genome editing with CRISPR)Kathy - Science Ambassadors ProgramDickson - Street ArtVincent - End Polio Now Listener Pick of the Week Ross - Three PhD Comics on Nature vs Science (one, two, three)Ricardo - Demographic Party Trick Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv

Thu, 19 Dec 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17337/ https://edoc.ub.uni-muenchen.de/17337/1/Darisipudi_Venkata.pdf Darisipudi, Venkata Surya Narayana Murty ddc:610, ddc:600, Medizinische Fakultät

Summary and hypothesis Role of pro-inflammatory chemokines in diabetic nephropathy Beyond hemodynamic and metabolic abnormalities associated with diabetes, the role of inflammation in development and progression of diabetic nephropathy is well accepted. Recruitment and activation of macrophages in different renal compartment is considered to be hallmark of all inflammation in diabetic nephropathy. Although recruitment of macrophages to the renal compartment has been extensively studied, the exact mechanisms involved are still to be explored. The chemokine-chemokine receptor interactions are implicated to be mainly responsible for trafficking and infiltration of different monocytes and macrophages. Contribution of macrophages to the development of DN can be addressed in either by inhibiting chemokines or chemokine receptor associated with diabetes. We hypothesized that inhibition of CCL2 may inhibit macrophages infiltrating into different compartments in kidney and inhibition started at earlier stage of disease progression may show more beneficial effects than CCL2 blockade at late stage of DN. To address the involvement of additional chemokine receptors we hypothesized that blocking CCR5 and CCR2 simultaneously might have some additive or synergistic effects. Role of homeostatic chemokines in diabetic nephropathy Homeostatic chemokies are mainly involved in hematopoeisis, immune cell survival and adaptive immune responses. CXCL12 attracted our attention as it is being extensively studied and reported to be responsible for different functions like stem cell survival and homing and trafficking to different compartments. The role of CXCL12 in diabetic nephropathy has not been explored yet. CXCL12 is constitutively expressed by different renal cells. It may contribute to tissue repair and inhibit disease progression by stem cell recruitment or may cause increased tissue fibrosis and aggravate the disease. We hypothesized that CXCL12 plays role in development and progression of diabetic nephropathy. In order to address this question we used CXCL12 blocker in a mouse model of diabetic nephropathy.

Chemokines remain attractive therapeutic targets for modulating inflammatory diseases in all areas of medicine including acute and chronic kidney disease. Industry has launched huge programs for the development of chemokine antagonists, and clinical trials with chemokine and chemokine receptor antagonists are ongoing. However, chemokine biology remains an area of unexpected discoveries. Here we discuss a number of questions which need to be addressed to further explore the potential of chemokine antagonism in renal inflammation: Why does renal expression of chemokines and chemokine receptors not always correlate with their functional significance? Why does chemokine antagonism only partially reduce renal leukocyte counts? Will antagonist combinations be more effective in reducing renal inflammation? What are the functional roles of homeostatic chemokines and atypical, nonsignaling chemokine receptors in renal inflammation? And finally, what classes of chemokine antagonists are available to address these questions experimentally? Copyright (C) 2009 S. Karger AG, Basel

The global burden of chronic kidney diseases remains an ongoing medical challenge. Therapies that can halt or reverse advanced renal injury are not yet available. Increasing numbers of patients progress to the end-stage renal failure and require renal replacement therapy, the latter being associated with significant mortality, a lower quality of life, and high costs for national health systems. Thus, new treatment strategies that slow down, halt or even revert progressive renal damage are requested. Chemokines and their receptors are involved in the pathogenesis of renal diseases. They mediate leukocytes and macrophages recruitment and activation during initiation as well as progression of renal inflammation. Infiltrating leukocytes are the major source for proinflammatory and profibrotic cytokines and are therefore critical for mediating fibroblast proliferation, differentiation into myofibroblasts, matrix production, and tubular atrophy. Recent advances in the understanding of the molecular mechanisms that regulate renal leukocyte recruitment suggest chemokines and chemokine receptors as novel targets for specific pharmacological intervention. The aim of the present thesis was to investigate the role of chemokine receptor CCR1 for the progression of chronic kidney diseases, e.g. Alport disease and diabetic nephropathy. Two different animal models were used: Col4A3-deficient mice and type 2 diabetic db/db mice with advanced diabetic nephropathy. We blocked CCR1 in Col4A3-deficient mice with BX417, a small molecule CCR1 antagonist, and BL5923, a novel orally available antagonist with a high specificity for human and murine CCR1 in uninephrectomized type 2 diabetic db/db mice, respectively. Treatment with BX471 (25mg/kg) from weeks 6 to 10 of life improved survival of COL4A3- deficient mice, characterized by glomerulosclerosis and subsequent progressive tubulointerstitial injury, leading to fatal end-stage renal disease (ESRD). Improvement was associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Ccl5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. When CCR1 was blocked with BL5923 (60mg/kg, b.i.d), the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with type 2 diabetes. Similarly, BL5923 orally administered from month 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, Tgf-β1, and collagen I-α1 when compared to untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for CCR1-dependent recruitment of interstitial macrophages for the progression of chronic kidney disease in Alport disease and diabetic nephropathy. These data identify CCR1 as a potential therapeutic target for Alport disease and late stage diabetic nephropathy or other progressive nephropathies associated with interstitial macrophage infiltrates.

Background: Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma. Methods: The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression. Results: Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells. Conclusion: Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology of osteosarcoma, but also contradict aspects of previous reports describing the expression of these receptors in this tumor.

Background: The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5) melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-gamma or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods: These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN), were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-gamma or TNF-alpha was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO) was determined using GRIES reagent. Results: We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1 alpha and MIP-1 beta following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-gamma or TNF-alpha, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC), MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin-deficient (PKO) effector T cells induced macrophages to secrete nitric oxide (NO), providing an additional effector mechanism for T cell-mediated tumor regression. Conclusion: These data suggest two possible sources for chemokine secretion that stimulates macrophage recruitment to the site of tumor metastases. Both appear to be initiated by T cell recognition of specific antigen, but one is dependent on the tumor cells to produce the chemokines that recruit macrophages.

Chemokines and their receptors are involved in many aspects of immunity. Chemokine CX3CL1, acting via its receptor CX3CR1, regulates monocyte migration and macrophage differentiation as well as T cell-dependent inflammation. Two common, nonsynonymous polymorphisms in CX3CR1 have previously been shown to alter the function of the CX3CL1/CX3CR1 pathway and were suggested to modify the risk for asthma. Using matrix-assisted laser desorption/ionization time-of-flight technology, we genotyped polymorphisms Val249Ile and Thr280Met in a cross-sectional population of German children from Munich (n = 1,159) and Dresden ( n = 1,940). For 249Ile an odds ratio of 0.77 (95% confidence interval 0.63-0.96; p = 0.017) and for 280Met an odds ratio of 0.71 ( 95% confidence interval 0.56-0.89; p = 0.004) were found with atopy in Dresden but not in Munich. Neither polymorphism was associated with asthma. Thus, amino acid changes in CX3CR1 may influence the development of atopy but not asthma in German children. Potentially, other factors such as environmental effects may modify the role of CX3CR1 polymorphisms. Copyright (c) 2007 S. Karger AG, Basel.

Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease. Copyright (C) 2004 S. Karger AG, Basel.