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ELife Jul 2024We studied lysosomal Ca in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca ([Ca]) and increased [Ca] through mitochondrial ROS, which...
We studied lysosomal Ca in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca ([Ca]) and increased [Ca] through mitochondrial ROS, which was suppressed in -KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by KO. ER→lysosome Ca refilling occurred after lysosomal Ca release whose blockade attenuated LPS + PA-induced inflammasome. Subsequently, store-operated Caentry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K efflux whose inhibition reduced ER Ca content ([Ca]) and impaired [Ca] recovery. LPS + PA activated KCa3.1 channel, a Ca-activated K channel. Inhibitors of KCa3.1 channel or KO reduced [Ca], attenuated increase of [Ca] or inflammasome activation by LPS + PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca release sustained by ERlysosome Ca refilling and K efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.
PubMed: 38953285
DOI: 10.7554/eLife.87561 -
Lung India : Official Organ of Indian... Jul 2024
PubMed: 38953197
DOI: 10.4103/lungindia.lungindia_454_23 -
Journal of Leukocyte Biology Jul 2024Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte...
Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial NF-κB p65 and MAPK c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 hours after CLP-sepsis initiation. E-selectin, not VCAM-1, was expressed in glomeruli at the same time point. In a subset of mice at 72 hours after CLP-sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 hours after CLP-sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment.
PubMed: 38953175
DOI: 10.1093/jleuko/qiae146 -
Frontiers in Immunology 2024Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression....
BACKGROUND
Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression. However, this phenomenon is underexplored in clear-cell renal cell carcinoma (ccRCC).
METHODS
Using SVM machine learning, we identified core anoikis-related genes (ARGs) from ccRCC patient transcriptomic data. A LASSO Cox regression model stratified patients into risk groups, informing a prognostic model. GSVA and ssGSEA assessed immune infiltration, and single-cell analysis examined ARG expression across immune cells. Quantitative PCR and immunohistochemistry validated ARG expression differences between immune therapy responders and non-responders in ccRCC.
RESULTS
ARGs such as CCND1, CDKN3, PLK1, and BID were key in predicting ccRCC outcomes, linking higher risk with increased Treg infiltration and reduced M1 macrophage presence, indicating an immunosuppressive environment facilitated by anoikis resistance. Single-cell insights showed ARG enrichment in Tregs and dendritic cells, affecting immune checkpoints. Immunohistochemical analysis reveals that ARGs protein expression is markedly elevated in ccRCC tissues responsive to immunotherapy.
CONCLUSION
This study establishes a novel anoikis resistance gene signature that predicts survival and immunotherapy response in ccRCC, suggesting that manipulating the immune environment through these ARGs could improve therapeutic strategies and prognostication in ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Anoikis; Kidney Neoplasms; Single-Cell Analysis; Prognosis; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Transcriptome; Cell Line, Tumor; Biomarkers, Tumor; T-Lymphocytes, Regulatory; Gene Expression Profiling; Male; Multiomics
PubMed: 38953023
DOI: 10.3389/fimmu.2024.1427475 -
Frontiers in Immunology 2024P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and...
INTRODUCTION
P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and have been involved in similar physiological processes, such as pain and inflammation as well as various immune cell functions. While formation of P2X2/P2X3 heterotrimers produces a distinct pharmacological phenotype and has been well established, functional identification of a P2X4/P2X7 heteromer has been difficult and evidence for and against a physical association has been found. Most of this evidence stems, however, from model systems.
METHODS
Here, we used a P2X7-EGFP BAC transgenic mouse model as well as P2X4 and P2X7 knock-out mice to re-investigate a P2X4-P2X7 interaction in mouse lung by biochemical and immunohistochemical experiments as well as quantitative expression analysis.
RESULTS
No detectable amounts of P2X4 could be co-purified from mouse lung via P2X7-EGFP. In agreement with these findings, immuno-histochemical analysis using a P2X7-specific nanobody revealed only limited overlap in the cellular and subcellular localizations of P2X4 and P2X7 in both the native lung tissue and primary cells. Comparison of P2X4 and P2X7 transcript and protein levels in the respective gene-deficient and wild type mice showed no mutual interrelation between their expression levels in whole lungs. However, a significantly reduced expression was found in alveolar macrophages of mice.
DISCUSSION
In summary, our detailed analysis of the cellular and subcellular P2X4 and P2X7 localization and expression does not support a physiologically relevant direct association of P2X4 and P2X7 subunits or receptors .
Topics: Animals; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7; Mice; Lung; Mice, Knockout; Mice, Transgenic; Mice, Inbred C57BL; Protein Binding
PubMed: 38953020
DOI: 10.3389/fimmu.2024.1425938 -
Frontiers in Medicine 2024The role of macrophages in the symptomatic and structural progression of pulmonary fibrosis (PF) has garnered significant scholarly attention in recent years. This study...
BACKGROUND
The role of macrophages in the symptomatic and structural progression of pulmonary fibrosis (PF) has garnered significant scholarly attention in recent years. This study employs a bibliometric approach to examine the present research status and areas of focus regarding the correlation between macrophages and PF, aiming to provide a comprehensive understanding of their relationship.
METHODOLOGY
The present study employed VOSviewer, CiteSpace, and Microsoft Excel software to visualize and analyze various aspects such as countries, institutions, authors, journals, co-cited literature, keywords, related genes, and diseases. These analyses were conducted using the Web of Science core collection database.
RESULTS
A comprehensive collection of 3,479 records pertaining to macrophages and PF from the period of 1990 to 2023 was obtained. Over the years, there has been a consistent increase in research literature on this topic. Notably, the United States and China exhibited the highest level of collaboration in this field. Through careful analysis, the institutions, authors, and prominent journals that hold significant influence within this particular field have been identified as having the highest publication output. The pertinent research primarily concentrates on the domains of Biology and Medicine. The prevailing keywords encompass pulmonary fibrosis, acute lung injury, idiopathic pulmonary fibrosis, and others. Notably, TGFβ1, TNF, and CXCL8 emerge as the most frequently studied targets, primarily associated with signaling pathways such as cytokine-cytokine receptor interaction. Additionally, cluster analysis of related diseases reveals their interconnectedness with ailments such as cancer.
CONCLUSION
The present study employed bibliometric methods to investigate the knowledge structure and developmental trends in the realm of macrophage and PF research. The findings shed light on the introduction and research hotspots that facilitate a more comprehensive understanding of macrophages and PF.
PubMed: 38952862
DOI: 10.3389/fmed.2024.1374177 -
Biomaterials Research 2024Liver fibrosis is a wound-healing response to chronic liver injury, which may lead to cirrhosis and cancer. Early-stage fibrosis is reversible, and it is difficult to... (Review)
Review
Liver fibrosis is a wound-healing response to chronic liver injury, which may lead to cirrhosis and cancer. Early-stage fibrosis is reversible, and it is difficult to precisely diagnose with conventional imaging modalities such as magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, and ultrasound imaging. In contrast, probe-assisted molecular imaging offers a promising noninvasive approach to visualize early fibrosis changes in vivo, thus facilitating early diagnosis and staging liver fibrosis, and even monitoring of the treatment response. Here, the most recent progress in molecular imaging technologies for liver fibrosis is updated. We start by illustrating pathogenesis for liver fibrosis, which includes capillarization of liver sinusoidal endothelial cells, cellular and molecular processes involved in inflammation and fibrogenesis, as well as processes of collagen synthesis, oxidation, and cross-linking. Furthermore, the biological targets used in molecular imaging of liver fibrosis are summarized, which are composed of receptors on hepatic stellate cells, macrophages, and even liver collagen. Notably, the focus is on insights into the advances in imaging modalities developed for liver fibrosis diagnosis and the update in the corresponding contrast agents. In addition, challenges and opportunities for future research and clinical translation of the molecular imaging modalities and the contrast agents are pointed out. We hope that this review would serve as a guide for scientists and students who are interested in liver fibrosis imaging and treatment, and as well expedite the translation of molecular imaging technologies from bench to bedside.
PubMed: 38952717
DOI: 10.34133/bmr.0042 -
Biomaterials Research 2024Intervertebral discs (IVDs) have a limited self-regenerative capacity and current strategies for IVD regeneration are unsatisfactory. Recent studies showed that small...
Intervertebral discs (IVDs) have a limited self-regenerative capacity and current strategies for IVD regeneration are unsatisfactory. Recent studies showed that small extracellular vesicles derived from M2 macrophage cells (M2-sEVs) inhibited inflammation by delivery of various bioactive molecules to recipient cells, which indicated that M2-sEVs may offer a therapeutic strategy for the repair of IVDs. Herein, we investigated the roles and mechanisms of M2-sEVs on IVD regeneration. The in vitro results demonstrated that M2-sEVs inhibited pyroptosis, preserved cellular viability, and promoted migration of nucleus pulposus cells (NPCs). Bioinformatics analysis and verification experiments of microRNA (miR) expression showed that miR-221-3p was highly expressed in M2-sEVs. The mechanism of action was explored and indicated that M2-sEVs inhibited pyroptosis of NPCs through transfer of miR-221-3p, which suppressed the expression levels of phosphatase and tensin homolog and NOD-, LRR-, and pyrin domain-containing protein 3. Moreover, we fabricated decellularized ECM-hydrogel (dECM) for sustained release of M2-sEVs, which exhibited biocompatibility and controlled release properties. The in vivo results revealed that dECM-hydrogel containing M2-sEVs (dECM/M2-sEVs) delayed the degeneration of intervertebral disc degeneration (IDD) models. In addition to demonstrating a promising therapeutic for IDD, this study provided valuable data for furthering the understanding of the roles and mechanisms of M2-sEVs in IVD regeneration.
PubMed: 38952714
DOI: 10.34133/bmr.0047 -
Sudanese Journal of Paediatrics 2024Multisystem inflammatory syndrome of childhood (MIS-C) is a recently described entity in pediatrics post-COVID-19 pandemic. Hemophagocytic lymphohistiocytosis (HLH) is a...
Multisystem inflammatory syndrome of childhood (MIS-C) is a recently described entity in pediatrics post-COVID-19 pandemic. Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome caused by an unregulated proliferation of macrophages as well as T lymphocytes. Both entities can be considered overlapping, although distinct criteria for each can be found in the literature. Herein, we report a patient with MIS-C post-COVID-19 infection, complicated with HLH secondary to malaria from a blood transfusion.
PubMed: 38952618
DOI: 10.24911/SJP.106-1679595787 -
Frontiers in Cardiovascular Medicine 2024In recent years, the role of macrophages as the primary cell type contributing to foam cell formation and atheroma plaque development has been widely acknowledged.... (Review)
Review
In recent years, the role of macrophages as the primary cell type contributing to foam cell formation and atheroma plaque development has been widely acknowledged. However, it has been long recognized that diffuse intimal thickening (DIM), which precedes the formation of early fatty streaks in humans, primarily consists of lipid-loaded smooth muscle cells (SMCs) and their secreted proteoglycans. Recent studies have further supported the notion that SMCs constitute the majority of foam cells in advanced atherosclerotic plaques. Given that SMCs are a major component of the vascular wall, they serve as a significant source of microvesicles and exosomes, which have the potential to regulate the physiology of other vascular cells. Notably, more than half of the foam cells present in atherosclerotic lesions are of SMC origin. In this review, we describe several mechanisms underlying the formation of intimal foam-like cells in atherosclerotic plaques. Based on these mechanisms, we discuss novel therapeutic approaches that have been developed to regulate the generation of intimal foam-like cells. These innovative strategies hold promise for improving the management of atherosclerosis in the near future.
PubMed: 38952543
DOI: 10.3389/fcvm.2024.1381520