International Immunopharmacology

We used a new strategy to screen cytokines associated with SARS-CoV-2 infection. Cytokines that can classify populations in different states of SARS-CoV-2 infection were first screened in cross-sectional serum samples from 184 subjects by 2 statistical analyses. The resultant cytokines were then analyzed for their interrelationships and fluctuating features in sequential samples from 38 COVID-19 patients. Three cytokines, M-CSF, IL-8 and SCF, which were clustered into 3 different correlation groups and had relatively small fluctuations during SARS-CoV-2 infection, were selected for the construction of a multiclass classification model. This model discriminated healthy individuals and asymptomatic and nonsevere patients with accuracy of 77.4% but was not successful in classifying severe patients. Further searching led to a single cytokine, hepatocyte growth factor (HGF), which classified severe from nonsevere COVID-19 patients with a sensitivity of 84.6% and a specificity of 97.9% under a cutoff value of 1128 pg/ml. The level of this cytokine did not increase in nonsevere patients but was significantly elevated in severe patients. Considering its potent antiinflammatory function, we suggest that HGF might be a new candidate therapy for critical COVID-19. In addition, our new strategy provides not only a rational and effective way to focus on certain cytokine biomarkers for infectious diseases but also a new opportunity to probe the modulation of cytokines in the immune response.

This study characterizes the first clinical application of CIGB-258 in COVID-19 patients. CIGB-258 is an immunoregulatory peptide, derived from the cellular heat shock protein 60 (HSP60). Sixteen patients with COVID-19 in serious (31%) or critical (69%) conditions were included in this study. All critically ill patients recovered from the respiratory distress condition. Two of these patients had a fatal outcome due to nosocomial infections.The five seriously ill patients considerably improved. C-reactive protein (CRP) and interleukin-6 (IL-6) levels significantly decreased during treatment. CIGB-258 seems to be an effective and safe treatment option in COVID-19 patients under cytokine storm. TRIAL REGISTRATION: RPCEC00000313

Mycoplasma pneumoniae pneumonia (MPP) is a common type of pneumonia among school-aged children and adolescents. Jinzhen Oral Liquid (JZOL) and Azithromycin (AZ) are commonly used treatment options in traditional Chinese medicine (TCM) and Western medicine, respectively. There are several clinical and basic research reports on their solo effect against MPP, enabling their combined treatment to become possible. However, the mechanisms and specific pharmacodynamics of their combined therapy remain unclear. In this study, we conducted a mechanistic analysis of the combination of JZOL and AZ based on network target, elucidating their modular network regulatory mechanisms. The modular mechanisms involve four modules, including hormone response, cell differentiation and migration, signal transduction, oxygen and hypoxia response, centered by TNF signaling pathway-mediated regulation. Under the instruction of computational analysis, we conducted a randomized, double-blind, three-armed, parallel-controlled, multicenter clinical study of different doses of JZOL combined with AZ for the treatment of MPP in children. At the study endpoint, the median time to clinical recovery showed statistically significant differences, which were also observed between groups for time to complete fever remission, time to relief of cough/phlegm, effective rate of chest X-ray improvement, and rate of healing of TCM symptoms. During the treatment period, there were no statistically significant differences in the rates of adverse events, serious adverse events, or adverse reactions between the groups. Different doses of JZOL combined with AZ in the treatment of MPP in children have shown the effects of shortening the course of the disease, relieving the symptoms, and improving the prognosis. The research program composed of computational prediction and clinical trials can significantly accelerate the research and development process and identify more effective treatment with good safety, which is worthy of clinical promotion.

Sepsis, a leading cause of death in intensive care units (ICUs), is a complex systemic inflammatory response to infection with high morbidity and mortality. Its pathogenesis involves dysregulated inflammation, immune dysfunction, and metabolic alterations, particularly in lactate metabolism. This study employed bioinformatics analyses to explore sepsis mechanisms and identify potential therapeutic targets. We analyzed two GEO datasets and found the lactate metabolism pathway significantly enriched in sepsis patients. Seventeen key genes were identified and used to classify sepsis into two subtypes via WGCNA and consensus clustering. These subtypes exhibited distinct clinical and immune profiles. Seven hub genes (BPI, HGF, HP, LCN2, LTF, MMP8, RETN) showed differential expression between subtypes and may serve as diagnostic biomarkers. MMP8 was identified as a critical regulator in lactate metabolism, with associated miRNAs and transcription factors predicted. Single-cell analysis revealed altered immune cell compositions and interactions in sepsis patients. Our findings offer novel insights into sepsis pathogenesis and potential therapeutic strategies targeting lactate metabolism and immune regulation. Keywords: sepsis; lactate metabolism; bioinformatics; immune microenvironment

Sepsis is a global health priority. Despite thorough studies in mice models, its molecular and cellular basis remain unclear and there is no pharmacological effective treatment other than antimicrobial and supportive therapy. During sepsis, T cells exhaustion compromises patients outcome, and immune checkpoints (ICs) become crucial players in disease management. Here, a total of 425 patients with systemic inflammatory response criteria and 127 controls were studied. Soluble SIGLEC5 (sSIGLEC5) levels in plasma were higher in patients with sepsis compared to the other groups and even higher in those patients with septic-shock. sSIGLEC5 plasma levels were higher in non-survivors than in survivors and ROC curves analysis revealed sSIGLEC5 as a survival marker (cut-off [≤] 523.6 ng/mL). In vitro experiments illustrated how SIGLEC5 impaired CD8+ proliferation through binding to PSGL1. Blocking the SIGLEC5/PSGL1 axis reverted the latter effect. Mechanistically, SIGLEC5 overexpression was driven by HIF1. Exogenous sSIGLEC5 accelerated death and magnified acute lung injury in mice models. Our data demonstrates how plasma sSIGLEC5 level on admission predicts death and stratifies patients with sepsis. This molecule exhibits the hallmarks of an IC ligand.

Microglia, the resident immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis and responding to various pathological conditions1,2. Neuroinflammation, characterized by the activation of microglia and subsequent release of pro-inflammatory cytokines, has been implicated in the pathogenesis of numerous neurodegenerative diseases. Among these cytokines, chemokine (C-C motif) ligand 2 (CCL2) has gained significant attention due to its role in attracting immune cells and its potential contribution to neuronal inflammation. This review aims to comprehensively elucidate the involvement of microglial CCL2 in neuronal inflammation and its relevance to neurodegenerative diseases. We discuss the molecular mechanisms underlying CCL2 production, its receptors on neurons, and the downstream signaling pathways that initiate and perpetuate neuroinflammation. Furthermore, we explore the bidirectional communication between microglia and neurons, highlighting how neuronal dysfunction can trigger microglial CCL2 release and subsequent immune responses3-5. Additionally, we examine the implications of CCL2-mediated neuroinflammation in neurodegenerative disorders such as Alzheimers disease6,7, Parkinsons disease8, and amyotrophic lateral sclerosis. Lastly, we discuss potential therapeutic strategies targeting the microglial CCL2 axis to modulate neuroinflammation and ameliorate neurodegenerative processes.

COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1, anti-IL-6, anti-TNF, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNF, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.

Severe infection-induced cytokine storm is an urgent medical syndrome with high mortality. To date, no therapy is available. This study shows that high concentrations of lipopolysaccharide (LPS) induce cytokine storm within 48h and thus kill most experimental mice. Rapid, but not late dexamethasone administration remarkably inhibits cytokine storm and rescues LPS-treated mice. Monocytes and macrophages are the major source of cytokine storm. In these cells, pro-inflammatory genes (i.e., Tnf, Il6 and Il1{beta}) have preassembled RNA polymerase II (RNA Pol II), but stay at the pause stage of transcriptional elongation in the absence of stimulation. LPS rapidly activates transcription of these "pre-loaded" genes within 2h. Administration of dexamethasone within this time window inhibits RNA Pol II ser2 binding to the core promoters of pro-inflammatory genes and thus reduces LPS-induced cytokine transcription. Therefore, rapid utilization of dexamethasone might be efficacious to prevent severe bacterium-induced cytokine storm in clinical practice.

Sepsis is the leading systemic inflammatory response syndrome in worldwide, yet relatively little is known about the genes and signaling pathways involved in sepsis progression. The current investigation aimed to elucidate potential key candidate genes and pathways in sepsis and its associated complications. Next generation sequencing (NGS) dataset (GSE185263) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 348 sepsis samples and 44 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. Next, we made use of the g:Profiler to analyze gene ontology (GO) and REACTOME pathway. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Furthermore, we constructed miRNA-hub gene regulatory network and TF-hub gene regulatory network among hub genes utilizing miRNet and NetworkAnalyst online databases tool and Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis of hub genes through the pROC package in R statistical software. In total, 958 DEGs were identified, of which 479 were up regulated and 479 were down regulated. GO and REACTOME results showed that DEGs mainly enriched in regulation of cellular process, response to stimulus, extracellular matrix organization and immune system. The hub genes of PRKN, KIT, FGFR2, GATA3, ERBB3, CDK1, PPARG, H2BC5, H4C4 and CDC20 might be associated with sepsis and its associated complications. Predicted miRNAs (e.g., hsa-mir-548ad-5p and hsa-mir-2113) and TFs (e.g., YAP1 and TBX5) were found to be significantly correlated with sepsis and its associated complications. In conclusion, the DEGs, relative pathways, hub genes, miRNA and TFs identified in the current investigation might help in understanding of the molecular mechanisms underlying sepsis and its associated complications progression and provide potential molecular targets and biomarkers for sepsis and its associated complications.

There are currently no specific vaccine or drugs proven to be effective against COVID-19. Traditional Chinese herbal medicine has been integrated into the official therapeutic protocol against COVID-19 in China. Qing Fei Pai Du Tang (QFPDT) is a Chinese multi-herbal formula newly developed and specifically optimized for the treatment of COVID-19. Therapeutic administration of QFPDT resulted in an improved cure rate in mild to critically-ill patients. However, the immunological mechanism for the efficacy of QFPDT has been poorly understood. Furthermore, the feasibility of prophylactic use in uninfected individuals remain unconfirmed. We thus examined whether the administration of QFPDT at a dose lower than recommended for therapeutic use alters hematological and/or immunological measures in healthy individuals. We found that QFPDT elevates the plasma levels of IL-1{beta}, IL-18, TNF-, and IL-8, which are key mediators of acute inflammatory responses to ssRNA viruses. No apparent adverse effects were observed during the trial. Our finding suggests that the pharmacological action of QFPDT is associated with the upregulation of a subset of proinflammatory cytokines despite its clinical benefits for COVID-19 patients. We should therefore be careful in its prophylactic use in uninfected individuals until we have a better understanding of the immunopharmacological action of QFPDT through further clinical studies with larger cohorts.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is expressed by neurons and glial cells in the central nervous system (CNS). In the CNS, BDNF is responsible for neuroprotection and neurogenesis. Recent studies showed that the Fingolimod, the first oral medicine for relapsing-remitting multiple sclerosis (RR-MS), induces BDNF expression. Besides, It is well demonstrated that long noncoding RNAs (lncRNAs) have a pivotal role in gene regulation. This study is mainly focused on how Fingolimod treatment plays role in BDNF regulation in coordination with lncRNAs. An in-silico study was performed to predict BDNF-regulatory candidate lncRNAs using online tools. Then, the expression of BDNF-related lncRNAs was analyzed in patients with relapsing-remitting multiple sclerosis (RRMS) at baseline and after three months of Fingolimod treatment. Based on in silico results, two lncRNAs with potential regulatory functions on the BDNF including, Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX Transcript Antisense RNA (HOTAIR), and also natural antisense of BDNF were selected. Fingolimod treatment increased the expression of HOTAIR lncRNA; however, the BDNF antisense RNA (BDNF-AS) expression was reduced dramatically. Furthermore, the results indicate a positive correlation between HOTAIR and MALAT1 lncRNAs and BDNF. Also, after Fingolimod treatment, the patients EDSS scores were declined or remained unchanged, indicating disease hindrance by Fingolimod therapy. Altogether, fingolimod exerts protective roles in RRMS patients probably by the mediation of HOTIAR and BDNF-AS lncRNAs.

ObjectiveThe pathogenesis of sepsis is still unknown. Sepsis 3.0 points out that "how to define sepsis and septic shock itself is still a challenge". This study confirmed the inevitability and universality of Hyperdynamic microcirculation in sepsis, and put forward the detoxification mechanism of Hyperdynamic blood flow and the "Xinghuai Feng-Bernoulli warm shock" mechanism, that is, the pathogenic mechanism of sepsis. MethodsSepsis models of pigs, rabbits, Mice, rats and sheep were established by intravenous injection of lipopolysaccharide (LPS) and cecal ligation and perforation (CLP), and the changes of sublingual microcirculation velocity in the same branch before and after modeling were detected. SD rat model of mild sepsis was established to verify that the acceleration of blood flow is the manifestation of immune detoxification mechanism. ResultsThe blood flow in the same branch was accelerated after the animal sepsis model was established, which was more than doubled on average. The microcirculation blood flow accelerated before the change of cardiac output CO. Rats entered a toxic state after the rapid blood flow occurred, but they could heal themselves. ConclusionThe acceleration of microcirculation blood flow in sepsis is inevitable and universal, which is the cause of high output and low resistance of sepsis, and has the functions of accelerating detoxification and immunity. However, due to Bernoulli effect, it will cause oxygen exchange disorder, which is named "Xinghuai Feng-Bernoulli warm shock", ultimately leading to hypoxia. This is the primary pathogenic mechanism of early sepsis. Since the completion of this article in 2023, its principles have undergone multicenter, randomized, and double-blind clinical verification, achieving satisfactory results. The specifics will have to wait for the publication by the three Class A tertiary hospitals.

BackgroundVestibular Migraine (VM) is a complex neurological disorder with recurrent headaches and various vestibular symptoms. Although it severely affects patients quality of life, its causes and pathophysiology are still unclear, and effective treatments are scarce. The lack of data emphasizes the need for bioinformatics to find key genes and pathways in VM, which could help develop new diagnostic and treatment methods. MethodThe GSE109558 dataset was acquired from the Gene Expression Omnibus (GEO) database. To identify VM - related differentially expressed genes, screening was carried out through limma and Weighted Correlation Network Analysis (WGCNA).The functional analysis of VM - related differentially expressed genes was conducted using three bioinformatics approaches: Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Feature selection was further refined using lasso regression and random forest. Also, CIBERSORT was utilized to analyze the infiltration of immune cells, and Spearmans correlation analysis was employed to explore the correlations between diagnostic differentially expressed genes and immune cells.Finally, the Comparative Toxicogenomics Database (CTD) was utilized to search for corresponding drugs, and molecular docking was performed to explore potential therapeutic targets. ResultSix key feature genes (CABIN1, IFIT3, HEATR1, ARHGDIA, RAB11FIP4, and ZNF444) were identified as potential diagnostic markers for VM. Among these, CABIN1 demonstrated the highest diagnostic potential based on ROC curve performance, highlighting its promise as a diagnostic biomarker.Functional annotation of DEGs revealed their enrichment in biological processes related to inflammation, calcium ion channel regulation, and other pathways likely involved in VM pathophysiology. Through the CTD, drugs like Acetaminophen, bisphenol A, and Phenylephrine were identified. Molecular docking simulation was used to explore their potential therapeutic mechanisms for VM. ConclusionThis study offers important insights into the molecular mechanisms of VM and identifies six key feature genes, with CABIN1 standing out as a potential diagnostic marker.These findings pave the way for further research to validate the diagnostic and therapeutic implications of these genes and pathways.

This study aims to investigate whether palmatine has a potential effect on sepsis-related pyroptosis in patients through relevant signaling pathways. Initially, the study explores the differential genes associated with pyroptosis in sepsis patients, along with their related enrichment processes, biological behaviors, and functional pathways. Patients with sepsis pyroptosis are then classified into subgroups based on pyroptosis-related genes to analyze the biological differences between these subtypes. Furthermore, the signaling pathways and biological functions associated with palmatine are studied to assess whether there are functional similarities or overlaps with the signaling pathways and biological behaviors observed in patients with sepsis pyroptosis. Finally, the findings are validated through wet-lab experiments. The results reveal that the signaling pathways related to palmatine partially overlap with those observed in sepsis pyroptosis patients, indicating that palmatine may influence sepsis pyroptosis through these pathways. Parmatine may improve the prognosis of sepsis by affecting the immune function of PRKACA, PTGS2, NLRP3, HSP90AA1 and PTPN22.

Coronavirus disease 2019 (COVID-19), which is currently a global public health emergency and beyond vaccines as a prophylactic treatment, no specific and effective therapeutical treatments are available. COVID-19 induces a massive release of proinflammatory cytokines, which drives COVID-19 progression, severity, and mortality. In addition, bronchial epithelial cells are the first pulmonary cells activated by coronavirus-2 (SARS-Cov-2) leading to massive cytokine release, which can hyperactivate lung fibroblasts, resulting in pulmonary fibrosis, a phenomenon observed even in moderate COVID-19 survivors. This in vitro study tested the hypothesis that Virlaza, a herbal medicine, could inhibit the hyperactivation of human bronchial epithelial cells (BEAS-2B) and pulmonary fibroblasts (MRC-5) induced by SARS-Cov-2. BEAS-2B (5x104/mL/well) and MRC-5 (5x104/mL/well) cells were co-cultivated with 1ml of blood of a Sars-Cov-2 infected patient for 4 hours and Virlaza (1ug/mL) was added in the first minute of the co-culture. After 4 hours, the cells were recovered and used for analysis of cytotoxicity by MTT and for mRNA expression of P2X7 receptor E iNOS. The supernatant was used to measure ATP and cytokines. Sars-Cov-2 incubation resulted in increased release of ATP, IL-1beta, IL-6, IL-8, and TNF-alpha by BEAS-2B and MRC-5 cells (p<0.001). Treatment with Virlaza resulted in reduction of ATP, IL-1beta, IL-6, IL-8, and TNF-alpha release (p<0.001). In addition, Sars-Cov-2 incubation resulted in increased expression of P2X7 receptor and iNOS (p<0.001), which has been reversed by Virlaza (p<0.001). In conclusion, Virlaza presents important anti-inflammatory effects in the context of Sars-Cov-2 infection.

BackgroundSepsis is a systemic inflammatory syndrome (SIRS) caused by acute microbial infection with high mortality rate. The role of tumour necrosis factor (TNF-)-induced necroptosis in promoting the pathophysiology of sepsis has been identified. Effective prevention of necroptosis is expected to improve the prognosis of sepsis patients. MethodsWe conducted bioinformatics prediction of candidate drugs by analyzing differentially expressed genes of sepsis patients extracted from GEO database, combining library of integrated network-based cellular signatures (LINCS) L1000 perturbation database. Biological experiments based on TNF--induced necroptosis in cellular and mouse model were performed to verify the protection of candidate drugs from SIRS. Cell viability was measured by CellTiter-Glo luminescent ATP assay. Effects of linifanib on necroptosis were investigated by western blotting, immunoprecipitation, and in vitro RIPK1 kinase assay. Survival curve analysis of SIRS mice treated by linifanib was performed. ResultsA total of 16 candidate drugs was screened out through bioinformatics analysis. Our experiments demonstrated that linifanib effectively protected cells from necroptosis and rescued the death of SIRS mice from shock induced by TNF-. In vitro, linifanib directly suppressed RIPK1 kinase activity. In vivo, linifanib effectively reduced the overexpressed level of IL-6, a good marker of severity during severe sepsis, in the lung of SIRS mice. ConclusionWe provide preclinical evidence for the potential clinical utility of linifanib in sepsis. Study of drug repositioning using bioinformatical predictions combined with experimental validations provides novel strategies for the development of sepsis drug.

Ferroptosis is crucial in neuronal cell death, associated with various neurological disorders. However, the role of ferroptosis-related genes (FRGs) in ischaemic stroke (IS) has yet to be well elucidated. We downloaded IS-related gene information and FRGs from the Gene Expression Omnibus (GEO) and Ferritin databases (FerrDb). 22 IS-related DE-FRGs were obtained. Functional enrichment analysis showed that these genes involve multiple regulatory pathways related to IS pathogenesis, including redox, amino acid metabolism, and cell cycle. Subsequently, DUOX2, MDM2, EGFR, MAP3K14, and TRIM46 were identified as core marker genes among the 22 DE-FRGs by lasso and SVM-RFE algorithms. The construction of the nomogram using the five marker genes had excellent diagnostic value. In addition, CIBERSORT analysis showed that changes in the immune microenvironment of IS patients might be associated with TRIM46, MDM2, and DUOX2. In addition, a total of 66 drugs targeting two characteristic FRGs were obtained. The ceRNA networks revealed complex regulatory relationships based on characteristic FRGs. These findings provide new insights into the diagnosis and treatment of IS.

The occurrence of acute sepsis-associated lung injury (ALI) is closely related to vascular endothelial cell dysfunction, but the exact isoform of the functional syndecans (SDCs) located in the inner endothelial membrane of blood vessels and involved in regulating inflammation is not clear. The present study aimed to clarify whether SDC2 and/or 4 is involved in the inflammation process.Using the Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) were extracted and analyzed. A bioinformatic analysis was conducted using R language, gene ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) with the aim of predicting SDC2 and 4 expression levels. Subsequently, the expression profiles of these two proteins were examined after construction of a sepsis-associated ALI mmodel was constructed in both human lung vascular endothelial cells (HLVEC) and animal models under inflammatory conditions. Eventually, the transcription factors (TF) of SDC2/4 were predicted based on the available dataset, and their involvement in septic inflammation was indirectly assessed. The GSE 5883 microarray gene-chip data profile was found to be suitable for analyzing lipopolysaccharide (LPS)-induced endothelial inflammatory injury. After analyzing the DEGs, 224 and 102 genes were found to be up- and down-regulated, respectively. All DEGs were involved in modulating receptor ligand and signaling receptor activator activities, cytokine receptor binding in biological processes, such as responses to lipopolysaccharide (LPS) and molecules from bacterial origins, positive regulation of cell adhesion, and other functions. In the case of localization of cellular components, most DEGs were enriched in cytoplasmic ribonucleoprotein granules, transcription regulator complex, and membrane rafts and were involved in the tumor necrosis factor (TNF) signaling and cytokine receptor interaction pathways. When compared with the control group, SDC4 gene expression in the LPS group increased by 4.5-fold, and comparable results were found in terms of SDC2 gene expression. From an experimental aspect, SDC4 was found to be markedly up-regulated with respect to mRNA and protein expression levels in response to inflammatory injury; moreover, down-regulation of SDC4 could severely exacerbate inflammatory responses either in in vivo or in vitro models. Altogether, SDC4, rather than SDC2, was found to be involved in LPS-induced sepsis-associated ALI.

Sepsis remains a life-threatening condition with limited therapeutic options targeting immune dysregulation. The CD47-SIRP "dont eat me" signaling axis, well characterized in tumor immune evasion, has not been systematically investigated in the context of sepsis. In this study, we performed a targeted transcriptomic analysis of phagocytosis- and "dont eat me" -related genes using the GSE228541 dataset (14 sepsis patients, 15 healthy controls). We identified 8 significantly differentially expressed genes within the curated gene panel. Key changes included downregulation of CD47 (logFC = -0.88, FDR = 5.6 x 10-4) and marked upregulation of PRTN3 (logFC = 2.68, FDR = 6.1 x 10-4). Gene Ontology (GO) enrichment demonstrated prominent alterations in pathways including negative regulation of phagocytosis (GO:0050765, FDR = 7.6 x 10-22), endocytosis, and inflammatory responses. Co-expression network analysis identified SNX3, DYSF, and PLSCR1 as hub genes within this regulatory module. Immune infiltration analysis showed increased M1 macrophage polarization and neutrophil activation in sepsis. Using LASSO regression, we constructed a 6-gene diagnostic signature (PLSCR1, SNX3, DYSF, PRTN3, CSK, CD47) that discriminated sepsis from controls with good performance (AUC = 0.933 in the test subset). Downregulation of CD47 suggests impaired "self" recognition, which may contribute to aberrant phagocytosis during sepsis. Elevated PRTN3 is consistent with neutrophil activation and extracellular trap formation, linking innate immune activation to tissue injury. This targeted transcriptomic analysis reveals coordinated transcriptional reprogramming of phagocytosis-regulatory genes in sepsis and supports the CD47-SIRP axis as a candidate therapeutic target for further investigation.

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1{beta}, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs {beta}1, {beta}2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. 30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a substantial amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CSF questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.