-
Open Forum Infectious Diseases Jul 2024is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity.... (Review)
Review
is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.
PubMed: 38947739
DOI: 10.1093/ofid/ofae316 -
The alarmin IL-33 exacerbates pulmonary inflammation and immune dysfunction in SARS-CoV-2 infection.IScience Jun 2024Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In...
Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33 mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33 mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.
PubMed: 38947521
DOI: 10.1016/j.isci.2024.110117 -
Frontiers in Immunology 2024In spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk...
Identification and experimental validation of cuproptosis regulatory program in a sepsis immune microenvironment through a combination of single-cell and bulk RNA sequencing.
BACKGROUND
In spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk model to diagnose and predict the risk of sepsis. In addition, the cuproptosis-related genes were identified for targeted therapy.
METHODS
Single-cell sequencing analyses were used to characterize the cuproptosis activity score (CuAS) and intercellular communications in sepsis. Differential cuproptosis-related genes (CRGs) were identified in conjunction with single-cell and bulk RNA sequencing. LASSO and Cox regression analyses were employed to develop a risk model. Three external cohorts were conducted to assess the model's accuracy. Differences in immune infiltration, immune cell subtypes, pathway enrichment, and the expression of immunomodulators were further evaluated in distinct groups. Finally, various experiments, such as flow cytometry, Western blot, and ELISA, were used to explore the role of LST1 in sepsis.
RESULTS
ScRNA-seq analysis demonstrated that CuAS was highly enriched in monocytes and was closely related to the poor prognosis of sepsis patients. Patients with higher CuAS exhibited prominent strength and numbers of cell-cell interactions. A total of five CRGs were identified based on the LASSO and Cox regression analyses, and a CRG-based risk model was established. The lower riskScore cohort exhibited enhanced immune cell infiltration, elevated immune scores, and increased expression of immune modulators, indicating the activation of an antibacterial response. Ultimately, experiments demonstrated that LST1, a key gene in the risk model, was enhanced in the macrophage in response to LPS, which was closely related to the decrease of macrophage survival rate, the enhancement of apoptosis and oxidative stress injury, and the imbalance of the M1/M2 phenotype.
CONCLUSIONS
This study constructed a cuproptosis-related risk model to accurately predict the prognosis of sepsis. We further characterized the cuproptosis-related gene LST1 to provide a theoretical framework for sepsis therapy.
Topics: Sepsis; Humans; Single-Cell Analysis; Male; Female; Middle Aged; Prognosis; Sequence Analysis, RNA; Cellular Microenvironment; Aged
PubMed: 38947313
DOI: 10.3389/fimmu.2024.1336839 -
Frontiers in Cardiovascular Medicine 2024Hypertrophic Cardiomyopathy (HCM), a widespread genetic heart disorder, is largely associated with sudden cardiac fatality. Necroptosis, an emerging type of programmed...
BACKGROUND
Hypertrophic Cardiomyopathy (HCM), a widespread genetic heart disorder, is largely associated with sudden cardiac fatality. Necroptosis, an emerging type of programmed cell death, plays a fundamental role in several cardiovascular diseases.
AIM
This research utilized bioinformatics analysis to investigate necroptosis's implication in HCM.
METHODS
The study retrieved RNA sequencing datasets GSE130036 and GSE141910 from the Gene Expression Omnibus (GEO) database. It detected necroptosis-linked differentially expressed genes (NRDEGs) by reviewing both the gene set for necroptosis and the differently expressed genes (DEGs). The enriched signaling pathway of HCM was assessed using GSEA, while common DEGs were studied through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Concurrently, the Protein-Protein Interaction network (PPI) proved useful for identifying central genes. CIBERSORT facilitated evaluating the correlation between distinct immune cell-type prevalence and NRDEGs by analyzing immune infiltration patterns. Lastly, GSE141910 dataset validated the expression ranks of NRDEGs and immune-cell penetration.
RESULTS
The investigation disclosed significant enrichment and activation of the necroptosis pathway in HCM specimens. Seventeen diverse genes, including CYBB, BCL2, and JAK2 among others, were identified in the process. PPI network scrutiny classified nine of these genes as central genes. Results from GO and KEGG enrichment analyses showed substantial connections of these genes to pathways pertaining to the HIF-1 signaling track, necroptosis, and NOD-like receptor signaling process. Moreover, an imbalance in M2 macrophage cells in HCM samples was observed. Finally, CYBB, BCL2, and JAK2 emerged as vital genes and were validated using the GSE141910 dataset.
CONCLUSION
These results indicate necroptosis as a probable underlying factor in HCM, with immune cell infiltration playing a part. Additionally, CYBB, BCL2, JAK2 could act as potential biomarkers for recognizing HCM. This information forms crucial insights into the basic mechanisms of HCM and could enhance its diagnosis and management.
PubMed: 38947229
DOI: 10.3389/fcvm.2024.1293786 -
Research Square Jun 2024Background The gut microbiome is linked to brain pathology in cases of traumatic brain injury (TBI), yet the specific bacteria that are implicated are not well...
Background The gut microbiome is linked to brain pathology in cases of traumatic brain injury (TBI), yet the specific bacteria that are implicated are not well characterized. To address this gap, in this study, we induced traumatic brain injury (TBI) in male C57BL/6J mice using the controlled cortical impact (CCI) injury model. After 35 days, we administered a broad-spectrum antibiotics (ABX) cocktail (ampicillin, gentamicin, metronidazole, vancomycin) through oral gavage for 2 days to diminish existing microbiota. Subsequently, we inflicted a second TBI on the mice and analyzed the neuropathological outcomes five days later. Results Longitudinal analysis of the microbiome showed significant shifts in the diversity and abundance of bacterial genera during both acute and chronic inflammation. These changes were particularly dramatic following treatment with ABX and after the second TBI. ABX treatment did not affect the production of short-chain fatty acids (SCFA) but did alter intestinal morphology, characterized by reduced villus width and a lower count of goblet cells, suggesting potential negative impacts on intestinal integrity. Nevertheless, diminishing the intestinal microbiome reduced cortical damage, apoptotic cell density, and microglial/macrophage activation in the cortical and thalamic regions of the brain. Conclusions Our findings suggest that eliminating colonized gut bacteria via broad-spectrum ABX reduces neuroinflammation and enhances neurological outcomes in TBI despite implications to gut health.
PubMed: 38946944
DOI: 10.21203/rs.3.rs-4475195/v1 -
Advanced Science (Weinheim,... Jul 2024Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long-established inhibitor...
Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long-established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC-independent. Mechanistically, UK5099 abrogates mitochondria-NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL-1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3-driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.
PubMed: 38946607
DOI: 10.1002/advs.202307224 -
Chinese Medical Journal Jun 2024Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that...
BACKGROUND
Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that the vagus nerve exerts anti-inflammatory activity in many inflammatory diseases. Here, we aimed to identify the key molecule mediating the inflammatory process in ACLF and reveal the neuroimmune communication arising from the vagus nerve and immunological disorders of ACLF.
METHODS
Proteomic analysis was performed and validated in ACLF model mice or patients, and intervention animal experiments were conducted using neutralizing antibodies. PNU-282987 (acetylcholine receptor agonist) and vagotomy were applied for perturbing vagus nerve activity. Single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemical and immunofluorescence staining, and CRISPR/Cas9 technology were used for in vivo or in vitro mechanistic studies.
RESULTS
The unbiased proteomics identified C-X-C motif chemokine ligand 9 (CXCL9) as the greatest differential protein in the livers of mice with ACLF and its relation to the systematic inflammation and mortality were confirmed in patients with ACLF. Interventions on CXCL9 and its receptor C-X-C chemokine receptor 3 (CXCR3) improved liver injury and decreased mortality of ACLF mice, which were related to the suppressing of hepatic immune cells' accumulation and activation. Vagus nerve stimulation attenuated while vagotomy aggravated the expression of CXCL9 and the severity of ACLF. Blocking CXCL9 and CXCR3 ameliorated liver inflammation and increased ACLF-associated mortality in ACLF mice with vagotomy. scRNA-seq revealed that hepatic macrophages served as the major source of CXCL9 in ACLF and were validated by immunofluorescence staining and flow cytometry analysis. Notably, the expression of CXCL9 in macrophages was modulated by vagus nerve-mediated cholinergic signaling.
CONCLUSIONS
Our novel findings highlighted that the neuroimmune communication of the vagus nerve-macrophage-CXCL9 axis contributed to ACLF development. These results provided evidence for neuromodulation as a promising approach for preventing and treating ACLF.
PubMed: 38945689
DOI: 10.1097/CM9.0000000000003104 -
Experimental Eye Research Jun 2024Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no...
Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM.
PubMed: 38945519
DOI: 10.1016/j.exer.2024.109986 -
Cancer Letters Jun 2024The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This...
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
PubMed: 38945201
DOI: 10.1016/j.canlet.2024.217090 -
Biomaterials Jun 2024Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment...
Extracellular matrix (ECM) scaffold membranes have exhibited promising potential to better the outcomes of wound healing by creating a regenerative microenvironment around. However, when compared to the application in younger individuals, the performance of the same scaffold membrane in promoting re-epithelialization and collagen deposition was observed dissatisfying in aged mice. To comprehensively explore the mechanisms underlying this age-related disparity, we conducted the integrated analysis, combing single-cell RNA sequencing (scRNA-Seq) with spatial transcriptomics, and elucidated six functionally and spatially distinctive macrophage groups and lymphocytes surrounding the ECM scaffolds. Through intergroup comparative analysis and cell-cell communication, we characterized the dysfunction of Spp1+ macrophages in aged mice impeded the activation of the type Ⅱ immune response, thus inhibiting the repair ability of epidermal cells and fibroblasts around the ECM scaffolds. These findings contribute to a deeper understanding of biomaterial applications in varied physiological contexts, thereby paving the way for the development of precision-based biomaterials tailored specifically for aged individuals in future therapeutic strategies.
PubMed: 38944969
DOI: 10.1016/j.biomaterials.2024.122685