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.

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.

Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-α1β2. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.