Despite the high sepsis-associated mortality, effective and specific treatments remain limited. Using conventional antibiotics as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging due to increasing bacterial resistance, diminishing their efficacy and leading to adverse effects. We previously found that aloe-emodin (AE) exerts therapeutic effects on sepsis by reducing systemic inflammation and regulating the gut microbiota. Here, we investigated whether administering AE and TIE post-sepsis onset, using a cecal ligation and puncture (CLP)-induced sepsis model, extends survival and improves physiological functions. Survival rates, inflammatory cytokines, tissue damage, immune cell populations, ascitic fluid microbiota, and key signaling pathways were assessed. Combining AE and TIE significantly enhanced survival rates, and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Moreover, substantial improvements in survival rates of AE + TIE-treated mice (10% to 60%) within 168 h were observed relative to the CLP group. This combination therapy also effectively modulated inflammatory marker (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) levels and immune cell counts by decreasing those of B, NK, and TNFR2+ Treg cells, while increasing that of CD8+ T cells; alleviated tissue damage; reduced bacterial load in the peritoneal cavity; and suppressed the NF-κB signaling pathway. We also observed a significantly altered peritoneal cavity microbiota composition post-treatment, characterized by reduced pathogenic bacteria (Bacteroides) abundance. Our findings underscore the potential of AE + TIE in treating sepsis, and encourage further research and possible clinical implementations to surmount the limitations of TIE and amplify the therapeutic potential of AE.
Copyright © 2024 Su, Deng, Hu, Lin, Xie, Ye, Lin, Zhou, Wu and Zheng.

Our research team previously reported the immunomodulatory effects of kombucha fermentation liquid. This study investigated the protective effects of turmeric kombucha (TK) against lipopolysaccharide (LPS)-induced sepsis and its impact on the intestinal microbiota of mice. A turmeric culture medium without kombucha served as the control (TW). Non-targeted metabolomics analysis was employed to analyze the compositional differences between TK and TW. Qualitative analysis identified 590 unique metabolites that distinguished TK from TW. TK improved survival from 40 to 90%, enhanced thermoregulation, and reduced pro-inflammatory factor expression and inflammatory cell infiltration in the lung tissue, suppressing the NF-κB signaling pathway. TK also altered the microbiome, promoting Allobaculum growth. Our findings shed light on the protective effects and underlying mechanisms of TK in mitigating LPS-induced sepsis, highlighting TK as a promising anti-inflammatory agent and revealing new functions of kombucha prepared through traditional fermentation methods.
Copyright © 2024 Su, Tan, Wu, Zhou, Xu, Zhao, Lin, Deng, Xie, Lin, Ye and Yang.

Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33-/- mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33-/- mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.
© 2024 The Author(s).

Despite its high mortality, specific and effective drugs for sepsis are lacking. Decoy receptor 3 (DcR3) is a potential biomarker for the progression of inflammatory diseases. The recombinant human DcR3-Fc chimera protein (DcR3.Fc) suppresses inflammatory responses in mice with sepsis, which is critical for improving survival. The Fc region can exert detrimental effects on the patient, and endogenous peptides are highly conducive to clinical application. However, the mechanisms underlying the effects of DcR3 on sepsis are unknown. Herein, we aimed to demonstrate that DcR3 may be beneficial in treating sepsis and investigated its mechanism of action. Recombinant DcR3 was obtained in vitro. Postoperative DcR3 treatment was performed in mouse models of lipopolysaccharide- and cecal ligation and puncture (CLP)-induced sepsis, and their underlying molecular mechanisms were explored. DcR3 inhibited sustained excessive inflammation in vitro, increased the survival rate, reduced the proinflammatory cytokine levels, changed the circulating immune cell composition, regulated the gut microbiota, and induced short-chain fatty acid synthesis in vivo. Thus, DcR3 protects against CLP-induced sepsis by inhibiting the inflammatory response and apoptosis. Our study provides valuable insights into the molecular mechanisms associated with the protective effects of DcR3 against sepsis, paving the way for future clinical studies.
Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Macrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments differ. Utilizing single-cell RNA sequencing (scRNA-seq) data from mice, we tested the hypothesis that retinal and brain microglia exhibit distinct transcriptional profiles due to their unique microenvironments.
Eyes and brains from 2-4 month wildtype mice were combined (20 eyes; 3 brains) to yield one biologically diverse sample per organ. Each tissue was digested into single cell suspensions, enriched for immune cells, and sorted for scRNA-seq. Analysis was performed in Seurat v3 including clustering, integration, and differential expression. Multi-parameter flow cytometry was used for validation of scRNA-seq results. Lymphocytic choriomeningitis virus (LCMV) Clone 13, which produces a systemic, chronic, and neurotropic infection, was used to validate scRNA-seq and flow cytometry results in vivo.
Cluster analysis of integrated gene expression data from eye and brain identified 6 Tmem119 + P2ry12 + microglial clusters. Differential expression analysis revealed that eye microglia were enriched for more pro-inflammatory processes including antigen processing via MHC class I (14.0-fold, H2-D1 and H2-K1) and positive regulation of T-cell immunity (8.4-fold) compared to brain microglia. Multi-parameter flow cytometry confirmed that retinal microglia expressed 3.2-fold greater H2-Db and 263.3-fold more H2-Kb than brain microglia. On Day 13 and 29 after LCMV infection, CD8+ T-cell density was greater in the retina than the brain.
Our data demonstrate that the microenvironment of retina and brain differs, resulting in microglia-specific gene expression changes. Specifically, retinal microglia express greater MHC class I by scRNA-seq and multi-parameter flow cytometry, resulting in a possibly enhanced capability to stimulate CD8+ T-cell inflammation during LCMV infection. These results may explain tissue-specific differences between retina and brain during systemic viral infections and CD8+ T-cell driven autoimmune disease.
Copyright © 2024 Bloomfield, Gong, Droho, Makinde, Gurra, Stumpf, Kharel, Gadhvi, Winter, Cui, Cuda and Lavine.