Immunotherapy in the context of sepsis-induced immunological dysregulation.

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.

The role of platelets in central hubs of inflammation: A literature review.

Platelets are increasingly recognized for their multifaceted roles in inflammation beyond their traditional involvement in haemostasis. This review consolidates knowledge on platelets as critical players in inflammatory responses. This study did an extensive search of electronic databases and identified studies on platelets in inflammation, focusing on molecular mechanisms, cell interactions, and clinical implications, emphasizing recent publications. Platelets contribute to inflammation via surface receptors, release of mediators, and participation in neutrophil extracellular trap formation. They are implicated in diseases like atherosclerosis, rheumatoid arthritis, and sepsis, highlighting their interaction with immune cells as pivotal in the onset and resolution of inflammation. Platelets are central to regulating inflammation, offering new therapeutic targets for inflammatory diseases. Future research should explore specific molecular pathways of platelets in inflammation for therapeutic intervention.

NLRP6 negatively regulates host defense against polymicrobial sepsis.

Introduction: Sepsis remains a major cause of death in Intensive Care Units. Sepsis is a life-threatening multi-organ dysfunction caused by a dysregulated systemic inflammatory response. Pattern recognition receptors, such as TLRs and NLRs contribute to innate immune responses. Upon activation, some NLRs form multimeric protein complexes in the cytoplasm termed "inflammasomes" which induce gasdermin d-mediated pyroptotic cell death and the release of mature forms of IL-1ß and IL-18. The NLRP6 inflammasome is documented to be both a positive and a negative regulator of host defense in distinct infectious diseases. However, the role of NLRP6 in polymicrobial sepsis remains elusive. Methods: We have used NLRP6 KO mice and human septic spleen samples to examine the role of NLRP6 in host defense in sepsis. Results: NLRP6 KO mice display enhanced survival, reduced bacterial burden in the organs, and reduced cytokine/chemokine production. Co-housed WT and KO mice following sepsis show decreased bacterial burden in the KO mice as observed in singly housed groups. NLRP6 is upregulated in CD3, CD4, and CD8 cells of septic patients and septic mice. The KO mice showed a higher number of CD3, CD4, and CD8 positive T cell subsets and reduced T cell death in the spleen following sepsis. Furthermore, administration of recombinant IL-18, but not IL-1ß, elicited excessive inflammation and reversed the survival advantages observed in NLRP6 KO mice. Conclusion: These results unveil NLRP6 as a negative regulator of host defense during sepsis and offer novel insights for the development of new treatment strategies for sepsis.

Tongfu Lifei Decoction Attenuated Sepsis-Related Intestinal Mucosal Injury Through Regulating Th17/Treg Balance and Modulating Gut Microbiota.

Intestinal damage and secondary bacterial translocation are caused by the inflammatory response induced by sepsis. Tongfu Lifei (TLF) decoction has a protective effect on sepsis-related gastrointestinal function injury. However, the relation between gut microbiota, immune barrier, and sepsis under the treatment of TLF have not been well clarified yet. Here, rats were subjected to cecal ligation and puncture (CLP) to create a sepsis model. Subsequently, the TLF decoction was given to CLP rats by gavage, fecal microbiota transplantation (FMT), and antibiotic were used as positive control. TLF suppressed the inflammatory response and improved the pathological changes in the intestines of CLP rats. Besides, TLF promoted the balance of the percentage of the Th17 and Treg cells. Intestinal barrier function was also improved by TLF through enhancing ZO-1, and Occludin and Claudin 1 expression, preventing the secondary translocation of other gut microbiota. TLF dramatically boosted the gut microbiota's alpha- and beta-diversity in CLP rats. Moreover, it increased the relative abundance of anti-inflammatory gut microbiota and changed the progress of the glucose metabolism. In short, TLF regulated the gut microbiota to balance the ratio of Th17/Treg cells, reducing the inflammation in serum and intestinal mucosal injury in rats.

The immune landscape of sepsis and using immune clusters for identifying sepsis endotypes.

Background: The dysregulated immune response to sepsis still remains unclear. Stratification of sepsis patients into endotypes based on immune indicators is important for the future development of personalized therapies. We aimed to evaluate the immune landscape of sepsis and the use of immune clusters for identifying sepsis endotypes. Methods: The indicators involved in innate, cellular, and humoral immune cells, inhibitory immune cells, and cytokines were simultaneously assessed in 90 sepsis patients and 40 healthy controls. Unsupervised k-means cluster analysis of immune indicator data were used to identify patient clusters, and a random forest approach was used to build a prediction model for classifying sepsis endotypes. Results: We depicted that the impairment of innate and adaptive immunity accompanying increased inflammation was the most prominent feature in patients with sepsis. However, using immune indicators for distinguishing sepsis from bacteremia was difficult, most likely due to the considerable heterogeneity in sepsis patients. Cluster analysis of sepsis patients identified three immune clusters with different survival rates. Cluster 1 (36.7%) could be distinguished from the other clusters as being an "effector-type" cluster, whereas cluster 2 (34.4%) was a "potential-type" cluster, and cluster 3 (28.9%) was a "dysregulation-type" cluster, which showed the lowest survival rate. In addition, we established a prediction model based on immune indicator data, which accurately classified sepsis patients into three immune endotypes. Conclusion: We depicted the immune landscape of patients with sepsis and identified three distinct immune endotypes with different survival rates. Cluster membership could be predicted with a model based on immune data.

Mechanism of electro-acupuncture in alleviating intestinal injury in septic mice via polyamine-related M2-macrophage polarization.

Objective: The objective of this study was to investigate the impact of electro-acupuncture (EA) on sepsis-related intestinal injury and its relationship with macrophage polarization. Methods: A sepsis model was established using cecal ligation and puncture (CLP) to assess the effectiveness of EA. The extent of pathological injury was evaluated using Chiu's score, the expression of ZO-1 and Ocludin, and the impact on macrophage polarization was examined through flow cytometry and immunofluorescence staining. The expression of spermidine, one type of polyamine, and ornithine decarboxylase (ODC) was measured using ELISA and PCR. Once the efficacy was determined, a polyamine depletion model was created, and the role of polyamines was reassessed by evaluating efficacy and observing macrophage polarization. Results: EA treatment reduced the Chiu's score and increased the expression of ZO-1 and Ocludin in the intestinal tissue of septic mice. It inhibited the secretion of IL-1ß and TNF-α, promoted the polarization of M2-type macrophages, increased the secretion of IL-10, and upregulated the expression of Arg-1, spermidine, and ODC. However, after depleting polyamines, the beneficial effects of EA on alleviating intestinal tissue damage and modulating macrophage polarization disappeared. Conclusion: The mechanism underlying the alleviation of intestinal injury associated with CLP-induced sepsis by EA involves with the promotion of M2-type macrophage polarization mediated by spermidine expression.

Effector function and neutrophil cell death in the severity of sepsis with diabetes mellitus.

Sepsis, a life-threatening condition resulting from immune dysregulation, is typically triggered by bacterial infections and commonly coexists with diabetes mellitus. Neutrophils are the first responders to infection and require regulated activation to control pathogen and damage-associated molecular patterns. Dysregulation of neutrophil activation leads to uncontrolled inflammatory responses, often observed in both sepsis and diabetes patients. Neutrophil dysregulation, characterized by effector dysfunction and inadequate cell death processes, can serve as a biomarker for assessing sepsis severity, particularly in diabetic patients. This review provides information on the relationship between effector function, neutrophil cell death, and the severity of sepsis in individuals with diabetes mellitus, aiming to shed light on the mechanisms underlying sepsis progression. Topics covered in the review include an overview of effector function of neutrophil cells, mechanisms of neutrophil cell death, and dysregulation of effectors and neutrophil cell death processes in sepsis severity with diabetes mellitus.

CD5L as a promising biological therapeutic for treating sepsis.

Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L's important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.

γδ T cell profiling in a cohort of preterm infants reveals elevated frequencies of CD83+ γδ T cells in sepsis.

Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.

Exploring the relationship between HCMV serostatus and outcomes in COVID-19 sepsis.

Background: Sepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19. Methods: A multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis. Results: The prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival. Discussion: These findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8+ T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management. Conclusion: This study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis.

Towards personalized medicine: a scoping review of immunotherapy in sepsis.

Despite significant progress in our understanding of the pathophysiology of sepsis and extensive clinical research, there are few proven therapies addressing the underlying immune dysregulation of this life-threatening condition. The aim of this scoping review is to describe the literature evaluating immunotherapy in adult patients with sepsis, emphasizing on methods providing a "personalized immunotherapy" approach, which was defined as the classification of patients into a distinct subgroup or subphenotype, in which a patient's immune profile is used to guide treatment. Subgroups are subsets of sepsis patients, based on any cut-off in a variable. Subphenotypes are subgroups that can be reliably discriminated from other subgroup based on data-driven assessments. Included studies were randomized controlled trials and cohort studies investigating immunomodulatory therapies in adults with sepsis. Studies were identified by searching PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov, from the first paper available until January 29th, 2024. The search resulted in 15,853 studies. Title and abstract screening resulted in 1409 studies (9%), assessed for eligibility; 771 studies were included, of which 282 (37%) were observational and 489 (63%) interventional. Treatment groups included were treatments targeting the innate immune response, the complement system, coagulation and endothelial dysfunction, non-pharmalogical treatment, pleiotropic drugs, immunonutrition, concomitant treatments, Traditional Chinese Medicine, immunostimulatory cytokines and growth factors, intravenous immunoglobulins, mesenchymal stem cells and immune-checkpoint inhibitors. A personalized approach was incorporated in 70 studies (9%). Enrichment was applied using cut-offs in temperature, laboratory, biomarker or genetic variables. Trials often showed conflicting results, possibly due to the lack of patient stratification or the potential influence of severity and timing on immunomodulatory therapy results. When a personalized approach was applied, trends of clinical benefit for several interventions emerged, which hold promise for future clinical trials using personalized immunotherapy.

The post-septic peripheral myeloid compartment reveals unexpected diversity in myeloid-derived suppressor cells.

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.

The molecular landscape of sepsis severity in infants: enhanced coagulation, innate immunity, and T cell repression.

Introduction: Sepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need. Methods: To elucidate characteristics driving sepsis in infants, we assembled a multi-transcriptomic dataset from public microarray datasets originating from five independent studies pertaining to bacterial sepsis in infant < 6-months of age (total n=335). We utilized a COmbat co-normalization strategy to enable comparative evaluation across multiple studies while preserving the relationship between cases and controls. Results: We found good concordance with only two out of seven of the published adult sepsis gene signatures (accuracy > 80%), highlighting the narrow utility of adult-derived signatures for infant diagnosis. Pseudotime analysis of individual subjects' gene expression profiles showed a continuum of molecular changes forming tight clusters concurrent with disease progression between healthy controls and septic shock cases. In depth gene expression analyses between bacteremia, septic shock, and healthy controls characterized lymphocyte activity, hemostatic processes, and heightened innate immunity during the molecular transition toward a state of shock. Discussion: Our analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality.

Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC's RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.

γδ T cells: The first line of defense for neonates.

A distinct CD83-expressing subset of γδ T cells are enriched in preterm infants with sepsis, providing insights into their functional maturation dynamics in settings of homeostasis and disease (León-Lara et al. https://doi.org/10.1084/jem.20231987).

Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.

Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor ß-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Inflammatory immunity and bacteriological perspectives: A new direction for copper treatment of sepsis.

Copper is an essential trace element for all aerobic organisms because of its unique biological functions. In recent years, researchers have discovered that copper can induce cell death through various regulatory mechanisms, thereby inducing inflammation. Efforts have also been made to alter the chemical structure of copper to achieve either anticancer or anti-inflammatory effects. The copper ion can exhibit bactericidal effects by interfering with the integrity of the cell membrane and promoting oxidative stress. Sepsis is a systemic inflammatory response caused by infection. Some studies have revealed that copper is involved in the pathophysiological process of sepsis and is closely related to its prognosis. During the infection of sepsis, the body may enhance the antimicrobial effect by increasing the release of copper. However, to avoid copper poisoning, all organisms have evolved copper resistance genes. Therefore, further analysis of the complex relationship between copper and bacteria may provide new ideas and research directions for the treatment of sepsis.

Gene expression signatures in blood from a West African sepsis cohort define host response phenotypes.

Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a critical lack of data from low- and middle-income countries where the sepsis burden is increased which inhibits generalized strategies for therapeutic intervention. Here we perform RNA sequencing of whole blood to investigate longitudinal host response to sepsis in a Ghanaian cohort. Data dimensional reduction reveals dynamic gene expression patterns that describe cell type-specific molecular phenotypes including a dysregulated myeloid compartment shared between sepsis and COVID-19. The gene expression signatures reported here define a landscape of host response to sepsis that supports interventions via targeting immunophenotypes to improve outcomes.

The role and therapeutic potential of SIRTs in sepsis.

Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection. Abnormal activation of the immune system and disturbance of energy metabolism play a key role in the development of sepsis. In recent years, the Sirtuins (SIRTs) family has been found to play an important role in the pathogenesis of sepsis. SIRTs, as a class of histone deacetylases (HDACs), are widely involved in cellular inflammation regulation, energy metabolism and oxidative stress. The effects of SIRTs on immune cells are mainly reflected in the regulation of inflammatory pathways. This regulation helps balance the inflammatory response and may lessen cell damage and organ dysfunction in sepsis. In terms of energy metabolism, SIRTs can play a role in immunophenotypic transformation by regulating cell metabolism, improve mitochondrial function, increase energy production, and maintain cell energy balance. SIRTs also regulate the production of reactive oxygen species (ROS), protecting cells from oxidative stress damage by activating antioxidant defense pathways and maintaining a balance between oxidants and reducing agents. Current studies have shown that several potential drugs, such as Resveratrol and melatonin, can enhance the activity of SIRT. It can help to reduce inflammatory response, improve energy metabolism and reduce oxidative stress, showing potential clinical application prospects for the treatment of sepsis. This review focuses on the regulation of SIRT on inflammatory response, energy metabolism and oxidative stress of immune cells, as well as its important influence on multiple organ dysfunction in sepsis, and discusses and summarizes the effects of related drugs and compounds on reducing multiple organ damage in sepsis through the pathway involving SIRTs. SIRTs may become a new target for the treatment of sepsis and its resulting organ dysfunction, providing new ideas and possibilities for the treatment of this life-threatening disease.

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.