Immunosuppression In Sepsis Research Articles

Personalized, disease-stage specific, rapid identification of immunosuppression in sepsis

IntroductionData overlapping of different biological conditions prevents personalized medical decision-making. For example, when the neutrophil percentages of surviving septic patients overlap with those of non-survivors, no individualized assessment is possible. To ameliorate this problem, an immunological method was explored in the context of sepsis.MethodsBlood leukocyte counts and relative percentages as well as the serum concentration of several proteins were investigated with 4072 longitudinal samples collected from 331 hospitalized patients classified as septic (n=286), non-septic (n=43), or not assigned (n=2). Two methodological approaches were evaluated: (i) a reductionist alternative, which analyzed variables in isolation; and (ii) a non-reductionist version, which examined interactions among six (leukocyte-, bacterial-, temporal-, personalized-, population-, and outcome-related) dimensions.ResultsThe reductionist approach did not distinguish outcomes: the leukocyte and serum protein data of survivors and non-survivors overlapped. In contrast, the non-reductionist alternative differentiated several data groups, of which at least one was only composed of survivors (a finding observable since hospitalization day 1). Hence, the non-reductionist approach promoted personalized medical practices: every patient classified within a subset associated with 100% survival subset was likely to survive. The non-reductionist method also revealed five inflammatory or disease-related stages (provisionally named ‘early inflammation, early immunocompetence, intermediary immuno-suppression, late immuno-suppression, or other’). Mortality data validated these labels: both ‘suppression’ subsets revealed 100% mortality, the ‘immunocompetence’ group exhibited 100% survival, while the remaining sets reported two-digit mortality percentages. While the ‘intermediary’ suppression expressed an impaired monocyte-related function, the ‘late’ suppression displayed renal-related dysfunctions, as indicated by high concentrations of urea and creatinine.DiscussionThe data-driven differentiation of five data groups may foster early and non-overlapping biomedical decision-making, both upon admission and throughout their hospitalization. This approach could evaluate therapies, at personalized level, earlier. To ascertain repeatability and investigate the dynamics of the ‘other’ group, additional studies are recommended.

T-cell immunosuppression in sepsis is augmented by sciatic denervation-induced skeletal muscle atrophy.

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid-derived suppressor cells (MDSC), and T-cells in peritoneal and spleen were analysed using flow cytometry. DN-induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T-lymphocyte-associated antigen (CTLA)-4+ CD4+ T-cells, programmed death (PD)-1+ CD8+ T-cells, regulatory T-cells, and the CTLA-4+ regulatory T-cells was statistically significantly higher in DN-CLP mice than in sham-CLP mice. Skeletal muscle atrophy before sepsis triggers excessive Tcell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy.

Current research status and prospects of ginseng's regulatory effect on immune dysfunction caused by "acute deficiency syndrome" of sepsis

Sepsis is a prevalent critical illness observed in emergency intensive care unit (ICU), characterized by life-threatening organ dysfunction caused by infection-induced inflammatory immune disorders in the body. The suppression of immune function plays a crucial role in the development and progression of sepsis. Traditional Chinese medicine theory of "acute deficiency syndrome" in sepsis shares similarities with the concept of "immunosuppression". According to this theory, ginseng is frequently utilized in clinical treatment of sepsis due to its ability to invigorate vitality and strengthen the body, playing a crucial role in tonifying deficiency and improving the overall health of patients. This paper provides a detailed discussion of the pathophysiological mechanisms of sepsis immune dysfunction and its correlation with "acute deficiency syndrome" in traditional Chinese medicine. It summarizes the current state of modern pharmacological research on ginseng's impact on the body's immune function, discusses relevant research progress and shortcomings regarding ginseng's therapeutic effects on immunosuppression in sepsis, and proposes future research directions.

Treg and neutrophil extracellular trap interaction contributes to the development of immunosuppression in sepsis.

The excessive formation and release of neutrophil extracellular traps (NETs) in sepsis may represent a substantial mechanism contributing to multiorgan damage, which is associated with a poor prognosis. However, the precise role of NETs in mediating the transition from innate immunity to adaptive immunity during the progression of inflammation and sepsis remains incompletely elucidated. In this study, we provide evidence that, despite a reduction in the number of CD4+ T cells in the late stage of sepsis, there is a notable upregulation in the proportion of Tregs. Mechanistically, we have identified that NETs can induce metabolic reprogramming of naive CD4+ T cells through the Akt/mTOR/SREBP2 pathway, resulting in enhanced cholesterol metabolism, thereby promoting their conversion into Tregs and augmenting their functional capacity. Collectively, our findings highlight the potential therapeutic strategy of targeting intracellular cholesterol normalization for the management of immunosuppressed patients with sepsis.

HMGB1 promotes neutrophil PD-L1 expression through TLR2 and mediates T cell apoptosis leading to immunosuppression in sepsis

Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1)activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression.

Identification of qualitative characteristics of immunosuppression in sepsis based on immune-related genes and immune infiltration features

ObjectiveSepsis is linked to high morbidity and mortality rates. Consequently, early diagnosis is crucial for proper treatment, reducing hospitalization, and mortality rates. Additionally, over one-fifth of sepsis patients still face a risk of death. Hence, early diagnosis, and effective treatment play pivotal roles in enhancing the prognosis of patients with sepsis. MethodThe study analyzed whole blood data obtained from patients with sepsis and control samples sourced from three datasets (GSE57065, GSE69528, and GSE28750). Commonly dysregulated immune-related genes (IRGs) among these three datasets were identified. The differential characteristics of these common IRGs in the sepsis and control samples were assessed using the REO-based algorithm. Based on these differential characteristics, samples from eight Gene Expression Omnibus (GEO) databases (GSE57065, GSE69528, GSE28750, GSE65682, GSE69063, GSE95233, GSE131761, and GSE154918), along with three ArrayExpress databases (E-MTAB-4421, E-MTAB-4451, and E-MTAB-7581), were categorized and scored. The effectiveness of these differential characteristics in distinguishing sepsis samples from control samples was evaluated using the AUC value derived from the receiver operating characteristic curve (ROC) curve. Furthermore, the expression of IRGs was validated in peripheral blood samples obtained from patients with sepsis through qRT-PCR. ResultsAmong the three training datasets, a total of 84 common dysregulated immune-related genes (IRGs) were identified. Utilizing a within-sample relative expression ordering (REOs)-based algorithm to analyze these common IRGs, differential characteristics were observed in three reverse stable pairs (ELANE-RORA, IL18RAP-CD247, and IL1R1-CD28). In the eight GEO datasets, the expression of ELANE, IL18RAP, and IL1R1 demonstrated significant upregulation, while RORA, CD247, and CD28 expression exhibited notable downregulation during sepsis. These three pairs of immune-related marker genes displayed accuracies of 95.89% and 97.99% in distinguishing sepsis samples among the eight GEO datasets and the three independent ArrayExpress datasets, respectively. The area under the receiver operating characteristic curve ranged from 0.81 to 1.0. Additionally, among these three immune-related marker gene pairs, mRNA expression levels of ELANE and IL1R1 were upregulated, whereas the levels of CD247 and CD28 mRNA were downregulated in blood samples from patients with sepsis compared to normal controls. ConclusionThese three immune-related marker gene pairs exhibit high predictive performance for blood samples from patients with sepsis. They hold potential as valuable auxiliary clinical blood screening tools for sepsis.

Immunosuppression in Sepsis: Biomarkers and Specialized Pro-Resolving Mediators.

Severe infection can lead to sepsis. In sepsis, the host mounts an inappropriately large inflammatory response in an attempt to clear the invading pathogen. This sustained high level of inflammation may cause tissue injury and organ failure. Later in sepsis, a paradoxical immunosuppression occurs, where the host is unable to clear the preexisting infection and is susceptible to secondary infections. A major issue with sepsis treatment is that it is difficult for physicians to ascertain which stage of sepsis the patient is in. Sepsis treatment will depend on the patient's immune status across the spectrum of the disease, and these immune statuses are nearly polar opposites in the early and late stages of sepsis. Furthermore, there is no approved treatment that can resolve inflammation without contributing to immunosuppression within the host. Here, we review the major mechanisms of sepsis-induced immunosuppression and the biomarkers of the immunosuppressive phase of sepsis. We focused on reviewing three main mechanisms of immunosuppression in sepsis. These are lymphocyte apoptosis, monocyte/macrophage exhaustion, and increased migration of myeloid-derived suppressor cells (MDSCs). The biomarkers of septic immunosuppression that we discuss include increased MDSC production/migration and IL-10 levels, decreased lymphocyte counts and HLA-DR expression, and increased GPR18 expression. We also review the literature on the use of specialized pro-resolving mediators (SPMs) in different models of infection and/or sepsis, as these compounds have been reported to resolve inflammation without being immunosuppressive. To obtain the necessary information, we searched the PubMed database using the keywords sepsis, lymphocyte apoptosis, macrophage exhaustion, MDSCs, biomarkers, and SPMs.

The effect of artesunate to reverse CLP-induced sepsis immunosuppression mice with secondary infection is tightly related to reducing the apoptosis of T cells via decreasing the inhibiting receptors and activating MAPK/ERK pathway

T cells play an important role in regulating immune system balance. Sepsis-associated immunosuppression causes apoptosis of T cells and a decrease in their number. Previously, artesunate was found to have an immunomodulatory effect on immunosuppression in model mice with cecal ligation and puncture (CLP)-induced sepsis. In the present study, mouse sepsis models of CLP and CLP with secondary infection were established and treated with artesunate in order to examine the effect of artesunate on adaptive immune response in sepsis-related immunosuppression. The results showed that artesunate treatment could increase the survival rate of CLP mice with secondary Pseudomonas aeruginosa infection, increase the bacterial clearance rate, and also increase the level of the pro-inflammatory cytokine TNF-α. In addition, artesunate resulted in an increase in the number of T cells, CD4+ T cells and CD8+ T cells, and inhibited CD4+ and CD8+ T-cell apoptosis. Artesunate was also found to inhibit the expression of the inhibitory receptors of PD-1, CTLA-4, and BTLA, but it did not affect the expression of Tim-3. Additionally, artesunate significantly increased the phosphorylated ERK level of CD4+ T cells and CD8+ T cells and inhibited mitochondrial pathway-mediated apoptosis in CLP mice with Pseudomonas aeruginosa infection. These findings reveal that artesunate has an immunomodulatory effect on the adaptive immune response in sepsis. These effects include an increase in the numbers of T cells, CD4+ T cells, and CD8+ T cells through inhibition of the expression of inhibitory receptors and promotion of the MAPK/ERK pathway.

Advances in the Study of Immunosuppressive Mechanisms in Sepsis.

Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.

Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis.

Lymphocyte apoptosis is a latent factor for immunosuppression in sepsis. Forkhead box protein P3 (FOXP3) can interact with RUNX family transcription factor 1 (RUNX1) in regulatory T cells. Our research was to probe whether RUNX1/FOXP3 axis affects immunosuppression in the process of sepsis by modulating T and B lymphocyte apoptosis. We constructed sepsis model in mice and mouse CD4+ T and CD19+ B lymphocytes. RUNX1 and FOXP3 expressions and apoptosis in cells were assessed by western blot, quantitative real-time PCR, and flow cytometer. Inflammation of serum and pathological damage was assessed by ELISA and H&E staining. Relationship between RUNX1 and FOXP3 was assessed by co-immunoprecipitation. The findings showed that RUNX1 ameliorated the survival rate, pathological damage, and decreased inflammation-related factors, and inhibited apoptosis of CD4+ T and CD19+ B cells in cecal ligation and puncture mice. Furthermore, RUNX1 up-regulated the viability and down-regulated apoptotic rate with the changed expressions of apoptosis-related molecules in lipopolysaccharide (LPS)-mediated CD4+ T and CD19+ B cells. Additionally, FOXP3 interacted with RUNX1, and its silencing decreased RUNX1 expression and reversed the inhibitory effect of RUNX1 on apoptosis of LPS-mediated CD4+ T and CD19+ B cells. In summary, the RUNX1/FOXP3 axis alleviated immunosuppression in sepsis progression by weakening T and B lymphocyte apoptosis.

Efferocytosis-inspired nanodrug treats sepsis by alleviating inflammation and secondary immunosuppression

Uncontrolled inflammation storm induced by sepsis may lead to severe organ dysfunction and secondary immunosuppression, which is one of the main reasons for high mortality and prolonged hospitalization of septic patients. However, there is a lack of effective treatments for it at present. Here, we report an efferocytosis-inspired nanodrug (BCN@M) to treat sepsis and secondary immunosuppression via regulating the macrophage function. Bioactive molecular curcumin was loaded with bovine serum albumin and then coated with the damaged erythrocyte membrane derived from septic mice. It was found that the septic erythrocytes promoted the efferocytosis signal and BCN@M uptake efficiency by macrophages. The well-constructed BCN@M nanodrug reduced the hyperinflammation in sepsis and restored the bacterial clearance ability of macrophage in the secondary immunosuppression state. This study highlights BCN@M as an efferocytosis-inspired nanodrug to alleviate hyperinflammation and secondary immunosuppression of sepsis.

Interferon-γ regulates immunosuppression in septic mice by promoting the Warburg effect through the PI3K/AKT/mTOR pathway

BackgroundThe main cause of high mortality from sepsis is that immunosuppression leads to life-threatening organ dysfunction, and reversing immunosuppression is key to sepsis treatment. Interferon γ (IFNγ) is a potential therapy for immunosuppression of sepsis, promoting glycolysis to restore metabolic defects in monocytes, but the mechanism of treatment is unclear.MethodsTo explore the immunotherapeutic mechanism of IFNγ, this study linked the Warburg effect (aerobic glycolysis) to immunotherapy for sepsis and used cecal ligation perforation (CLP) and lipopolysaccharide (LPS) to stimulate dendritic cells (DC) to establish in vivo and in vitro sepsis models, Warburg effect inhibitors (2-DG) and PI3K pathway inhibitors (LY294002) were used to explore the mechanism by which IFNγ regulates immunosuppression in mice with sepsis through the Warburg effect.ResultsIFNγ markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. IFNγ-treated mice had significantly increased the percentages of positive costimulatory receptor CD86 on Dendritic cells expressing and expression of splenic HLA-DR. IFNγ markedly reduced DC-cell apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax. CLP-induced formation of regulatory T cells in the spleen was abolished in IFNγ -treated mice. IFNγ treatment reduced the expression of autophagosomes in DC cells. IFNγ significant reduce the expression of Warburg effector-related proteins PDH, LDH, Glut1, and Glut4, and promote glucose consumption, lactic acid, and intracellular ATP production. After the use of 2-DG to suppress the Warburg effect, the therapeutic effect of IFNγ was suppressed, demonstrating that IFNγ reverses immunosuppression by promoting the Warburg effect. Moreover, IFNγ increased the expression of phosphoinositide 3-kinases (PI3K), protein kinase B (Akt), rapamycin target protein (mTOR), hypoxia-inducible factor-1 (HIF-1α), pyruvate dehydrogenase kinase (PDK1) protein, the use of 2-DG and LY294002 can inhibit the expression of the above proteins, LY294002 also inhibits the therapeutic effect of IFNγ.ConclusionsIt was finally proved that IFNγ promoted the Warburg effect through the PI3K/Akt/mTOR pathway to reverse the immunosuppression caused by sepsis. This study elucidates the potential mechanism of the immunotherapeutic effect of IFNγ in sepsis, providing a new target for the treatment of sepsis.

Peripheral immune cell death in sepsis based on bulk RNA and single-cell RNA sequencing

BackgroundImmune cell activation in early sepsis is beneficial to clear pathogens, but immune cell exhaustion during the inflammatory response induces immunosuppression in sepsis. Here, we studied the relationship between immune cell survival status and the prognosis of sepsis patients. MethodsSepsis patients admitted to our hospital with a diagnosis time of less than 24 h were recruited. RNA sequencing technologies were used to study functional alterations in various immune cells in peripheral blood mononuclear cells (PBMCs) from sepsis patients. Flow cytometry and electron microscopy were performed to study cell apoptosis and morphological alterations. ResultsA total of 68 sepsis patients with complete data were enrolled and divided into survival (45 patients) and death (23 patients) groups according to their prognosis. Patients in the death group had significantly increased lactic acid levels compared with those in the survival group, but there was no significant difference in other physiological and coagulation functional indicators between the two groups. Bulk RNA sequencing showed that cell death-related pathways and biomarkers were highly enriched and activated in the PBMCs of the death group than that in the survival group. Signs of mitochondrial damage, autophagosomes, cell surface damage and cell surface pore forming were also more pronounced in PBMCs from the death group under electron microscopy. Further single-cell RNA sequencing revealed that cell death occurred mainly in myeloid cells rather than lymphocytes at the early stage of sepsis; cell death patterns of destructive necrosis and pyroptosis were predominant in neutrophils, and apoptosis, autophagy and ferroptosis with less damage to the surroundings were predominant in monocytes. ConclusionCell death mainly occurs in monocytes and neutrophils in the PBMCs of sepsis at the early stage. The study provides a perspective for the immunotherapy of early sepsis targeting immune cell death.

Effect of circulating exosomes in patients with sepsis on T cell function

To investigate the effect of circulating exosomes (EXO) on T cell function in patients with sepsis. Plasma EXO were obtained by ultracentrifugation from 10 patients with sepsis admitted to the emergency intensive care unit of Guangdong Provincial People's Hospital Affiliated to Southern Medical University. Transmission electron microscopy observation, nanoparticle tracking analysis (NTA), and Western blotting were used to detect EXO markers to identify their characteristics. Furthermore, peripheral blood mononuclear cells (PBMC) were isolated from the peripheral blood of 5 healthy volunteers, primary T cells were sorted by magnetic beads and expanded in vitro. After 24 hours of intervention with different doses (0, 1, 2.5, 5, 10 mg/L) of circulating EXO in patients with sepsis, T-cell activity was assessed using a cell counting kit-8 (CCK-8). The expression of T cell activation indicators CD69 and CD25 were observed using flow cytometry. Additional evaluations were performed on immunosuppressive indicators including the expression of programmed cell death 1 (PD-1) in CD4+ T cells and the proportion of regulatory T cell (Treg). The identification results confirmed that the successful isolation of EXO from the plasma of sepsis patients. The expression level of circulating EXO in sepsis patients was higher than that in healthy control group (mg/L: 48.78±5.14 vs. 22.18±2.25, P < 0.01). After 24 hours of intervention with 5 mg/L of plasma EXO from sepsis patients, T cells activity began to show suppression [(85.84±0.56)% vs. (100.00±0.00)%, P < 0.05]. As the dosage increased, after 24 hours of intervention with 10 mg/L of EXO, T cells activity was significantly suppressed [(72.44±2.36)% vs. (100.00±0.00)%, P < 0.01]. Compared with the healthy control group, after T cells intervention with plasma EXO from sepsis patients, the expression of early activation marker CD69 was significantly reduced [(52.87±1.29)% vs. (67.13±3.56)%, P < 0.05]. Meanwhile, there was an upregulation of PD-1 expression in T cells [(57.73±3.06)% vs. (32.07±0.22)%, P < 0.01] and an increase in the proportion of Treg [(54.67±1.19)% vs. (24.60±3.51)%, P < 0.01]. However, the expression of the late activation marker CD25 remained stable [(84.77±3.44)% vs. (85.93±2.32)%, P > 0.05]. Circulating EXO in sepsis patients induce T cell dysfunction, which may be a novel mechanism lead to immunosuppression in sepsis.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients presenting sepsis-induced immunosuppression: The GRID randomized controlled trial

PurposeSeptic shock is associated in some patients with a profound immunosuppression. We hypothesized that GM-CSF would reduce the occurrence of ICU-acquired infections in immunosuppressed septic patients. MethodsRandomized double-blind trial conducted between 2015 and 2018. Adult patients, admitted to ICU, with severe sepsis or septic shock presenting with sepsis-induced immunosuppression defined by mHLA-DR < 8000 ABC (antibodies bound per cell) at day 3 were included. Patients were randomized to receive GM-CSF 125 μg/m2 or placebo for 5 days at a 1:1 ratio. The primary outcome was the difference in the number of patients presenting≥1 ICU-acquired infection at day 28 or ICU discharge. ResultsThe study was prematurely stopped because of insufficient recruitment. A total of 98 patients were included, 54 in the intervention group and 44 in the placebo group. The two groups were similar except for a higher body mass index and McCabe score in the intervention group. No significant difference was observed between groups regarding ICU-acquired infection (11% vs 11%, p = 1.000), 28-day mortality (24% vs 27%,p = 0.900), or the number or localization of the ICU infections. ConclusionGM-CSF had no effect on the prevention of ICU-acquired infection in sepsis immunosuppression, but any conclusion is limited by the early termination of the study leading to low number of included patients.

Regulatory role of the programmed cell death 1 signaling pathway in sepsis induced immunosuppression.

Sepsis is a multiple organ dysfunction syndrome caused by the host's immune response to infection, with extremely high incidence and mortality. Immunosuppression is an essential pathophysiological alteration that influences the clinical treatment and prognosis of sepsis. Recent studies have suggested that the programmed cell death 1 signaling pathway is involved in the formation of immunosuppression in sepsis. In this review, we systematically present the mechanisms of immune dysregulation in sepsis and elucidate the expression and regulatory effects of the programmed cell death 1 signaling pathway on immune cells associated with sepsis. We then specify current research developments and prospects for the application of the programmed cell death 1 signaling pathway in immunomodulatory therapy for sepsis. Several open questions and future research are discussed at the end.

The Effect of Secreted IL-10 from Mesenchymal Stem Cell on Immune Checkpoint Molecules.

Immunosuppression in sepsis is hypothesized to result from the increased expression of the immune checkpoint molecules programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). PD-1 and PD-L1 blockade therapies have been reported to increase survival in septic animals. Currently, the interleukin (IL)-10 within mesenchymal stem cell (MSC) secretome is known for its immunomodulatory capacity. To study the effect of IL-10 within MSC secretome on the expression of immune checkpoints in the rat model of sepsis. Methods: We used 48 male Rattus norvegicus rats in this research and divided them into four groups: sham (rats without sepsis induction and treatment), control (sepsis-induced rats without treatment), T1 (sepsis-induced rats treated with 150 μL of secreted IL-10 from MSC), and T2 (sepsis-induced rats treated with 300 μL of secreted IL-10 from MSC). Forty-eight hours after sepsis induction, we terminated the rats and collected the blood to examine the PD-1 and PD-L1 expression levels. We found a decrease in the relative expression of PD-1 in the septic rat group given 150 μL and 300 μL of secreted IL-10 from MSC compared to the control group, but the decrease was not significant. We also found a decrease in the relative expression of PD-L1 mRNA in the septic rat group given 150 μL and 300 μL of secreted IL-10 from MSC compared to the control group. Administering secreted IL-10 from MSC reduces the expression of PD-1 and PD-L1 in sepsis. These findings suggest that MSC secretome can improve the immunosuppression in sepsis.

NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated Tcells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.

Understanding sepsis-induced immunosuppression and organ dysfunctions: from immunosuppression to immunotherapy

Sepsis is a life-threatening condition caused by dysregulated host immune response to infection, leading to persistent inflammation followed by immunosuppression. Sepsis represents a substantial global health problem owing to protracted inflammation, immune suppression, and susceptibility to nosocomial infections. Despite continuing progress in the development of antibiotics, fluid resuscitation, and other supportive care therapies, no specific immunomodulatory drugs or immunotherapeutic adjuncts for the treatment of sepsis are available to date. The advances in tertiary care facilities and patient care have improved the survival of sepsis patients in the initial hyper-inflammatory phase of sepsis. However, the majority of sepsis patients succumb later due to prolong immunosuppression. The sepsis-induced immune dysregulation and its long-term effects on mortality are under meticulous investigations that are still poorly defined. Sepsis leads to the impaired functions of the innate and adaptive immune systems. The exhaustion of T cells, reduced expression of human leukocytes antigen (HLA)-DR on monocytes, and induced uncontrolled apoptosis of immune cells have been reported as hallmark features of sepsis. Sepsis-induced immune cell apoptosis of immune cells is a primary contributing factor to the immunosuppression in sepsis. Preclinical studies have identified several new therapeutic targets for therapy in sepsis, including monoclonal antibodies (Abs) and anti-apoptotic agents to reduce T cells exhaustion, immune cells apoptosis, and restoring immune cells functions. Recent studies have centered on immune-modulatory therapy. The review article will focus solely on sepsis’ effects on innate and adaptive cells functions that contribute to immunosuppression. Finally, it is discussed how immune cells responsible for immunosuppression might be directly targeted to provide potential therapeutic benefits in treating sepsis and improving long-term survival.

Of mice and men: Laboratory murine models for recapitulating the immunosuppression of human sepsis.

Prolonged immunosuppression is increasingly recognized as the major cause of late phase and long-term mortality in sepsis. Numerous murine models with different paradigms, such as lipopolysaccharide injection, bacterial inoculation, and barrier disruption, have been used to explore the pathogenesis of immunosuppression in sepsis or to test the efficacy of potential therapeutic agents. Nonetheless, the reproducibility and translational value of such models are often questioned, owing to a highly heterogeneric, complex, and dynamic nature of immunopathology in human sepsis, which cannot be consistently and stably recapitulated in mice. Despite of the inherent discrepancies that exist between mice and humans, we can increase the feasibility of murine models by minimizing inconsistency and increasing their clinical relevance. In this mini review, we summarize the current knowledge of murine models that are most commonly used to investigate sepsis-induced immunopathology, highlighting their strengths and limitations in mimicking the dysregulated immune response encountered in human sepsis. We also propose potential directions for refining murine sepsis models, such as reducing experimental inconsistencies, increasing the clinical relevance, and enhancing immunological similarities between mice and humans; such modifications may optimize the value of murine models in meeting research and translational demands when applied in studies of sepsis-induced immunosuppression.