International Immunopharmacology

Sepsis is a life-threatening condition driven by dysregulated immune responses and multi-organ dysfunction, with limited treatments targeting its underlying pathophysiology. Growing evidence highlights fatty acid-binding protein 4 (FABP4) as a key mediator of inflammation and organ injury in sepsis. In this study, we investigated the therapeutic potential of an anti-FABP4 monoclonal antibody (6H2) in a murine endotoxemia model induced by lipopolysaccharide (LPS). Treatment with 6H2 significantly attenuated systemic inflammation, as evidenced by modulated leukocyte responses, and provided substantial tissue protection in the liver, lungs, kidneys, and heart, reducing histopathological damage. Our findings identify 6H2 as a promising novel therapeutic intervention for sepsis. Author SummaryTitleTherapeutic Potential of Anti-FABP4 Antibody (6H2) in Sepsis: Protection Against Systemic Inflammation and Organ Damage Key Findings- Sepsis, a life-threatening inflammatory condition, lacks targeted therapies. We investigated 6H2, a monoclonal antibody against fatty acid-binding protein 4 (FABP4), in a mouse model of sepsis. - 6H2 treatment significantly reduced sepsis severity, improved survival, and attenuated organ damage in the liver, lungs, kidneys, and heart. - Histopathological analysis revealed restored tissue integrity in 6H2-treated mice, with reduced inflammation and cell death compared to controls. - Complete Blood Count showed modulated immune responses, including altered leukocyte counts, suggesting 6H2s role in rebalancing inflammation. SignificanceFABP4 is a key driver of sepsis-related inflammation and organ dysfunction. Our study demonstrates that 6H2 not only mitigates systemic inflammation but also provides multi-organ protection, offering a promising therapeutic strategy for sepsis. These findings support further preclinical and clinical development of FABP4-targeted therapies.

Mitochondrial damage and neuroinflammation belong to two of the most important pathological factors in multiple neurological disorders. However, the effect of mitochondrial damage of microglia on microglial activation under pathological conditions has remained unclear. In our current study, we used BV2 microglia as a cellular model to determine the effects of mitochondrial electron transport chain (ETC) inhibitors on LPS-induced inflammatory responses of microglia. We found that all of the three mitochondrial ETC inhibitors, including rotenone, sodium azide and antimycin A, significantly inhibited LPS-induced inflammatory responses of the microglia, assessed by determinations of the protein or mRNA levels of IL-1{beta}, IL-6, TNF-, iNOS and COX2. Nuclear translocation of NF-{kappa}B p65 subunit does not appear to play an important role in the mitochondrial ETC inhibition-produced suppression of microglial activation. Instead, our study found that the mitochondrial ETC inhibitors significantly attenuated not only the LPS-induced increase in the TREM1 levels - an amplifier of inflammatory process, but also the LPS-induced increase in the ratio of phosphorylated STAT3 / STAT3. In summary, our study has suggested that mitochondrial ETC inhibition of microglia can lead to suppression of LPS-induced microglial activation, which may be mediated by the inhibitory effects of mitochondrial ETC inhibition on the LPS-induced increases in the level of TREM1 and the ratio of p-STAT3 / STAT3. These findings have provided valuable information for elucidating the relationships between mitochondrial damage and neuroinflammation in multiple neurological diseases.

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

BackgroundNeonatal sepsis, a systemic inflammatory response to infection, is a major cause of morbidity and mortality in newborns. Neutrophil extracellular trap formation (NETosis), while crucial for pathogen clearance, can contribute to organ dysfunction in sepsis. This study aimed to identify key NETosis-related genes for prognostication in neonatal sepsis. MethodsWe analysed whole blood transcriptome datasets (GSE26440, GSE26378, GSE25504) from neonates with sepsis and controls. Differentially expressed NETosis genes (DE-NET genes) were identified, and a machine learning approach was used to select the most influential genes. A NET score model was constructed and validated using single-sample gene set enrichment analysis (ssGSEA). The models performance was evaluated using ROC analysis. The interplay between key-NET genes and the complement-coagulation (CC) system was investigated. Clinical samples were also collected for validation. ResultsSixteen DE-NET genes were identified, and LASSO further refined these to 8 key-NET genes. The key-NET gene signature and NET score model showed excellent predictive performance (AUCs > 89%) in distinguishing survivors from non-survivors. Mediation analysis revealed that key-NET gene expression precedes and potentially drives complement-coagulation activation. ConclusionsWe present an 8-gene prognostic model for risk stratification in neonatal sepsis, based on early blood transcript signatures in neonates. Our findings underscore the central role of NETosis in sepsis- induced coagulopathy, revealing potential therapeutic targets for intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/24313397v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@141c8ddorg.highwire.dtl.DTLVardef@1ea52f2org.highwire.dtl.DTLVardef@ebc63eorg.highwire.dtl.DTLVardef@1242a90_HPS_FORMAT_FIGEXP M_FIG C_FIG

Rational25-60% of septic patients experience relative adrenal insufficiency (RAI) and glucocorticoid (GC) is frequently used in septic patients. However, the efficacy of GC therapy and whether the GC therapy should be based on the status of RAI are highly controversial. Critical barriers include technical limitations in properly identifying RAI in septic patients and a lack of RAI animal model. ObjectivesWe established a new RAI animal model to test our hypothesis that precision medicine approach should be used for GC sepsis therapy - only applying GC to a subgroup of septic mice with RAI. MethodsWe generated SF1CreSR-BIfl/fl conditional knockout mice. The mice exhibited specific depletion of SR-BI expression in adrenal gland, resulting in a lack of production of inducible GC in response to ACTH stimulation or sepsis, but the mice had normal basal GC levels. Mice were treated with cecal ligation and puncture to develop sepsis. Mice were also supplemented with or without GC to study the effect of GC in sepsis therapy. Plasma and organs were collected for biochemical assays. BODIPY FL-conjugated Escherichia coli was used for phagocytosis assay. Macrophages were used to study effects of GC on inflammatory responses. Measurements and Main ResultsUsing SF1CreSR-BIfl/fl mice as a RAI model, we found that mice with RAI were susceptible to CLP-induced sepsis compared to controls (6.7% survival in SF1CreSR-BIfl/fl mice versus 86.4% in SR-BIfl/fl mice; p=0.0001). Supplementation of hydrocortisone significantly improved survival in CLP-treated SF1CreSR-BIfl/fl mice. Surprisingly, wild type mice receiving GC treatment exhibited significantly less survival compared to wild type mice without GC treatment. We further found that, in contrast to wild type mice which displayed a well-controlled systemic inflammatory response, the mice with RAI featured a persisted systemic response as shown by high levels of plasma inflammatory cytokines/chemokines 20 hours post CLP, and supplementation of GC kept the inflammatory response under control. In vitro analysis revealed that stress level of GC is required to suppress inflammatory response through modulating MAPK signaling in macrophages. ConclusionsWe demonstrate that RAI is a risk factor and an endotype for sepsis, and GC treatment benefits mice with RAI but harms mice without RAI. We further demonstrate that inducible GC functions to keep the systemic inflammatory response under control through modulating MAPK signaling, but mice with RAI lose such protection and supplementation of GC regains the protection. Our study provides a proof of concept to support the use of a precision medicine approach for sepsis therapy - selectively applying GC therapy for a subgroup of patients with RAI.

Heat stroke is a life-threatening illness and is related to systematic inflammation-induced multiple organ dysfunction. Available evidence indicates that the severity of the systematic inflammatory response in heat stroke may be related to the changes in immune regulation brought by heat acclimation. However, the mechanisms of heat acclimation are still unclear. Here, we assessed the differences in immunocyte subsets in the spleen and lymph nodes of heat-acclimated and unacclimated mice. A higher frequency of CD4+Foxp3+ Tregs was observed in heat-acclimated mice. Our results indicated that the improved heat tolerance exhibited during acute heat stress exposure was related to an increased number of Tregs. In heat-acclimated mice, an increase in the number of Tregs was able to mitigate the recruitment of neutrophils, inhibit the activation of neutrophils, and suppress the severity of acute inflammation. Increased differentiation and development of Tregs in peripheral immune organs in heat-acclimated mice might stem from enhanced expression of Foxp3 and PD-L1. Our results strongly suggest that the regulatory function of increased Tregs on neutrophils may be regulated through the PD-1/PD-L1 pathway. The anti-inflammatory effects of Tregs have never been studied in the context of heat stress-induced systemic inflammation. Thus, our results on immunoregulation involving Tregs in heat-acclimated mice might be significant for devising a potential treatment for systemic inflammatory response syndrome and heatstroke.

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.

BackgroundCOVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis. Since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes and that they are massively recruited to infected lungs, we investigated whether metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients. MethodsBased on prospective mortality outcome, 102 critically ill-hospitalized COVID-19 patients were divided into two groups: ICU-Survivors (ICU-S, n=36) and ICU-Non-survivors (ICU-NS, n=66). Blood samples were collected from patients and control subjects to explore correlations between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils for glycolytic activities and for apoptosis using high-throughput fluorescence imaging complemented with transcriptomic analyses. Stratified survival analyses were conducted to estimate mortality risk associated with higher lactate among predefined subgroups. ResultsNeutrophil counts were consistently higher in critically ill patients while exhibiting remarkably lower apoptosis. Transcriptomic analysis revealed miRNAs associated with downregulation of genes involved in neutrophils apoptosis. Both CT lung damage scores and neutrophil counts predicted mortality. Severinghaus fitting of hemoglobin oxygen saturation curve revealed a right-shift indicating lower oxygen capacity in non-survivors, which is consistent with lower blood-pH observed in the same group. Levels of blood lactate were increased in patients but significantly more in the ICU-NS relative to the control group. ROC analysis followed by Kaplan-Meyer survival analysis stratified to the obtained cut-off values showed that CT damage scores, neutrophil counts, and lactate levels are predictors of mortality within 15 days following blood collection. ConclusionThe current results implicate neutrophilia as a potential player in metabolic acidosis and deranged oxygen delivery associating SARS-CoV-2 infection thus contributing to mortality outcome.

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.

Sepsis is a systemic inflammatory response syndrome (SIRS) characterized by a dysregulated host response to infection that results in organ dysfunction. The response of neutrophils to early inflammation is critical, interferon regulatory factors 4 (IRF4) and interferon regulatory factors 5 (IRF5) are expressed in most cell types of the immune system, but the relationship between the role of IRF4 and IRF5 in preconditioning-protected septic peritonitis mouse model and neutrophils response remains unknown. In this study, we used an E.coli-induced septic peritonitis mouse model and zebrafish model to explore the relationship between neutrophil inflammation and IRF subtype changes in the process of septic peritonitis. Mechanistically, we found that the protein complex formed by polymorphonuclear neutrophils (PMN) and IRF5/MyD88 can secrete pro-inflammatory factors and directly kill invading bacteria. Author SummaryNumerous animal and clinical sepsis studies have shown that markedly impaired recruitment of neutrophils to sites of infection and failure to clear bacteria contribute to excessive inflammation and increased mortality in sepsis. In our previous work, we established an Escherichia coli (E.coli) lethal septic peritonitis model and a preconditioning-protected septic peritonitis mouse model. In the early stage of septic peritonitis, a large number of PMN infiltrate the peritoneal cavity, which produces an inflammatory response to invasive bacteria. In this study, the switching process between pro-inflammatory and anti-inflammatory attracted our attention. Our research shows that IRF5-IRF4 regulatory axis leads to a PMN phenotype switch in sepsis and the expression of IRF5 and IRF4 was related to PMN pro-inflammatory (N1 type) and anti-inflammatory (N2 type) phenotypes, respectively.

RationalLymphopenia and neutrophil/lymphocyte ratio may have prognostic value in coronavirus disease 2019 (COVID-19) severity. ObjectiveWe sought to investigate the representation of neutrophil subsets in severe and critical COVID-19 patients based on Intensive Care Units (ICU) and non-ICU admission. MethodsWe developed a multi-parametric neutrophil profiling strategy based on known neutrophil markers to distinguish COVID-19 phenotypes in critical and severe patients. ResultsOur results showed that 80% of ICU patients develop strong myelemia with CD10-CD64+ immature neutrophils. Cellular profiling revealed two distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or the Interleukin-3 receptor alpha (CD123), both significantly overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1-expressing immature neutrophils positively correlated with clinical severity, with the cytokine storm (IL-1{beta}, IL-6, IL-8, TNF), and with intravascular coagulation. Importantly, high proportions of LOX-1+-immature neutrophils are associated with high risks of severe thrombosis. ConclusionsTogether these data suggest that point of care enumeration of LOX-1-immature neutrophils might help distinguish patients at risk of thrombosis complication and most likely to benefit from intensified anticoagulant therapy.

Cytokine storms are associated with severe pathological damage and death in some diseases. Excessive activation of M1 macrophages and the subsequent secretion of pro-inflammatory cytokines are a major cause of cytokine storms. Therefore, promoting the polarization of M2 macrophages to restore immune balance is a promising therapeutic strategy for treating cytokine storm syndrome (CSS). This study was aimed at investigating the potential protective effects of leucine on lipopolysaccharide (LPS)-induced CSS in mice and exploring the underlying mechanisms. CSS was induced by LPS administration in mice, which were concurrently administered leucine orally. In vitro, BMDMs were polarized to M1 and M2 phenotypes with LPS and IL-4, respectively, and treated with leucine. Leucine decreased mortality in mice treated with lethal doses of LPS. Specifically, leucine decreased M1 polarization and promoted M2 polarization, thus diminishing pro-inflammatory cytokine levels and ameliorating CSS in mice. Further studies revealed that leucine induced macrophage polarization through the mechanistic target of rapamycin complex 1 (mTORC1)/liver X receptor (LXR) pathway, which synergistically enhanced the expression of the IL-4-induced M2 marker Arg1 and subsequent M2 polarization. In summary, this study revealed that leucine ameliorates CSS in LPS mice by promoting M2 polarization through the mTORC1/LXR/Arg1 signaling pathway. Our findings indicate that a fundamental link between metabolism and immunity contributes to the resolution of inflammation and the repair of damaged tissues.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy caused by antibodies against the aquaporin 4(AQP4) in end-feet of astrocytes. Breakdown of the blood-brain barrier (BBB) allowing ingress of AQP4 antibodies into the central nervous system (CNS) plays a key role in NMOSD. Although IL-6 blockade therapies such as satralizumab are effective in NMOSD, the therapeutic mechanism of IL-6 blockade, especially with respect to BBB disruption, are not fully understood because of the lack of the human models that are specialized to evaluate the BBB function. We constructed new in vitro human BBB models for evaluating continued barrier function, leukocyte transmigration and intracerebral transferability of IgGs utilizing the newly established triple co-culture system. In vitro and vivo experiments revealed that NMO-IgG increased intracerebral transferability of satralizumab, and that satralizumab suppressed the NMO-IgG-induced transmigration of T cells and barrier dysfunction. These results suggest that satralizumab, which can pass through the BBB in the presence of NMO-IgG, suppresses the barrier dysfunction and the disrupting controlled cellular infiltration at the BBB, leading to prevention of onset of NMOSD. One sentence summarySatralizumab and IL-6 blockade prevent lymphocyte migration and barrier dysfunction induced by NMO-IgG in EAE and novel triple co-culture BBB models.

Extensive evidence has revealed the crucial roles of long non-coding RNAs (lncRNAs) in acute lung injury (ALI). This study aimed to explore the mechanism of lncRNA SNHG1 in lipopolysaccharides (LPS)-induced ALI. RT-qPCR was employed to test the levels of SNHG1, miR-421 and TIMP3 in A549 cells. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. ELISA assay was adopted to examine the levels of inflammatory-related cytokines, including IL-1{beta}, IL-6 and TNF-. The binding sequences of miR-421 and SNHG1 or TIMP3 were predicted using starBase software. Then dual-luciferase reporter and RIP assays were adopted to verify the interaction between miR-421 and SNHG1 or TIMP3. The protein level of TIMP3 was measured by western blotting. It was found that LPS stimulation downregulated SNHG1 level and SNHG1 addition decreased viability, and induced apoptosis as well as promoted inflammatory responses in LPS-treated A549 cells. SNHG1 could sponge miR-421 and SNHG1 protected A549 cells from LPS-induced injury via inhibiting miR-421. Moreover, TIMP3 was a target of miR-421. MiR-421 silence protected A549 cells against the LPS-triggered inhibition in viability, and promotion in apoptosis and inflammatory responses. SNHG1 could upregulate TIMP3 through acting as a ceRNA of miR-421 in A549 cells. Altogether, the present study elaborated that SNHG1 inhibited LPS-stimulated ALI by modulating the miR-421/TIMP3 axis.

Objectivethe biomarkers performance for diagnosis and severity stratification of sepsis has not been properly evaluated anew using the SEPSIS-3 criteria introduced in 2016. We evaluated the accuracy of 21 biomarkers classically tested in sepsis research to identify infection, sepsis, and septic shock in surgical patients classified using SEPSIS-3. Methodsfour groups of adult surgical patients were compared: post-surgical patients with no infection, patients with infection but no sepsis, patients with sepsis, and patients with septic shock were recruited prospectively from the surgery departments and surgical ICUs from four Spanish hospital. The area under the curve (AUC) to differentiate between groups was calculated for each biomarker. ResultsA total of 187 patients were recruited (50 uninfected post-surgery controls, 50 patients with infection, 47 with sepsis and 40 with septic shock). The AUCs indicated that none of the biomarkers tested was accurate enough to differentiate those patients with infection from the uninfected controls. In contrast, procalcitonin, lipocalin 2, pentraxin 3, IL-15, TNF-, IL-6, angiopoietin 2, TREM-1, D-dimer and C-reactive protein yielded AUCs > 0.80 to discriminate the patients with sepsis or septic shock from those with no infection. C-reactive protein and IL-6 were the most accurate markers to differentiate plain infection from sepsis (AUC = 0.82). Finally, our results revealed that sepsis and septic shock shared similar profiles of biomarkers. ConclusionRevaluation in the "SEPSIS-3 era" identified the scenarios where biomarkers do and do not provide useful information to improve the management of surgical patients with infection or sepsis.

The poly-ADP-ribose polymerase (PARP) superfamily consists of 17 members, which regulate many biological processes in physiological or pathological conditions, such as DNA damage repair, anti-viral responses, and development of adaptive immune cells. Among them, PARP14 is the biggest member, containing two RNA recognition motifs at the N-terminal, three macro-domains, one WWE domain, and one PARP domain at the C-terminal, which was reported to regulate IL4/STAT6 signaling in adaptive immune cells. However, whether PARP14 participates in regulating host inflammatory response remains unclear. In a previous study, we observed that virus infection and LPS treatment induced the transcription of Parp14. By comparing the primary macrophages derived from Parp14 KO and WT mice, we found that some inflammatory cytokines were significantly induced in KO macrophages. Still, the expression of Ifnb1 had no significant difference compared to the WT macrophages. RNA-seq analysis showed that the KO group had a more robust inflammatory response but a weaker innate immune response upon stimulation. We validated these results by performing a knockdown of Parp14 in RAW 264.7 cells. Moreover, the survival time of the KO mice was much shorter than that of the WT group upon LPS injection. Transcription factor enrichment analysis indicated that nuclear factor-kappaB1 (NF-{kappa}B1) may be the main reason for increasing the production of these inflammatory cytokines. As expected, the up-regulation was deleted upon the treatment of the inhibitor of NF-{kappa}B, JSH23. These data imply that PARP14 regulates inflammatory responses through the NF-{kappa}B pathway.

Infection would lead to temperature increase in the affected region or entire human body, in order to weaken the pathogens, such as virus, or activate the immune system. As an alternative therapy with extensive application for various diseases, hyperthermia (HT) can regulate the release of pro-inflammatory cytokines and the antiviral activity of immune system. However, existing studies have found that overheating impairs healthy tissues and immune cells. The study puts forth a modified HT treatment, thermal cycling-hyperthermia (TC-HT), looking into its effect on immunomodulation and cellular viabilities. It shows that TC-HT can reduce the secretion of pro-inflammatory cytokines, induced by lipopolysaccharide (LPS) both ex vivo and in vitro, and elevate the efficacy of U-937 macrophages in clearing herpes simplex virus type 1 (HSV-1) in vitro. Furthermore, via optimizing its parameters, TC-HT can boost the efficacy of U-937 macrophage in clearing HSV-1, which may be attributed to the enhancement of actin polymerization and phagocytosis activity via TC-HT. In sum, TC-HT outperforms HT in safety and therapeutic effect in immunomodulation, shedding light on its potential in the treatment of immunological diseases.

The protein tyrosine phosphatase SHP-1 is a key negative regulator in cancer by dephosphorylating multiple target molecules. Specially in the NF{kappa}B signaling, where NF{kappa}B1/Rela dimer translocate to the nucleus and activate target gene transcription, SHP-1 inhibits the phosphorylation of Rela, while its regulation on NF{kappa}B1 has been unknown, especially in pathogen-induced inflammation. Chinese tongue sole, a representative flatfish, has been widely used as a genomics and disease model. Using the teleost and cellular model, we revealed for the first time that SHP-1 inhibits NF{kappa}B1 phosphorylation and nuclear translocation by interacting with NF{kappa}B1, thereby suppressing NF{kappa}B signaling to inhibit bacterial inflammation. In addition, we showed that SHP-1 decreased mortality and alleviated histopathological deterioration, manifested in the inhibition of immune-related pathways and secretion of pro- inflammatory cytokines. Using cellular model, SHP-1 overexpression reduced macrophages M1 polarization, phagocytosis, and oxidative stress, while silencing SHP- 1 exhibited opposite effects. Our findings systematically dissect the functions of SHP- 1 and provide mechanistic insights into the control of inflammation-related diseases. TeaserSHP-1 help maintain the cellular and individual homeostasis by inhibiting the excessive inflammation and immunity via regulating the NF{kappa}B signaling.

Nitric oxide, synthesised by three isoforms of Nitric Oxide synthases viz., nNOS by neurons, eNOS by endothelial cells and iNOS by phagocytes, performs a wide variety of biological functions in neurons, vascular endothelial cells and immune cells. Interaction between inducible nitric oxide synthase (iNOS) and Nitric oxide synthase interacting protein (NOSIP) was observed both in human monocytes and mouse macrophages and in cell free systems by biophysical methods. A novel mutation in nitric oxide synthase interacting protein (NOSIP) determined NO levels produced by human monocytes and was associated with disease severity in Sepsis patients. The study reveals NOSIP as an important regulator of inflammation by virtue of its ability to influence nitric oxide production both in mice and in humans and opens up novel avenues for therapeutic strategies against acute inflammation. While the influence of this novel NOSIP polymorphism in cardio-vascular and neuronal functions could be a subject of future investigations, its role in determining disease severity and mortality of the ongoing Covid 19 pandemic will be of immediate relevance.

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.